eurocombi3 – winchester 18 to 23 july 2005eurocombi3 – winchester 18th to 23rd july 2005 3rd...

EUROCOMBI3 – Winchester 18th to 23rd July 2005

Final Program...................................................................................................................... 3 Invited speakers ................................................................................................................ 13 ESCS publication award winner ....................................................................................... 16 Monday 18th July 2005 ..................................................................................................... 17

Libraries for Biological Effect ...................................................................................... 17 Chemistry and Micro-arrays ......................................................................................... 20 HT Materials Research ................................................................................................. 23 MCR’s........................................................................................................................... 27

Tuesday 19th July 2005 ..................................................................................................... 31 Microfluidics and HT Synthesis and Screening............................................................ 31 Combinatorial Biology.................................................................................................. 34 Young Researcher Presentations – sponsored by the Chemical Computing Group..... 38

Wednesday 20th July 2005 ................................................................................................ 46 Microwaves in HT Synthesis ........................................................................................ 46 Complex Library Synthesis........................................................................................... 50 Enabling Technologies and Informatics ....................................................................... 53

Thursday 21st July 2005 .................................................................................................... 59 Synthesis and screening of Combinatorial Libraries .................................................... 59 Supported Reagents ...................................................................................................... 62 ESCS Publication Award Lecture: Tandem Lecture .................................................... 64 Peptide Based Catalysis ................................................................................................ 65

Poster Presentations .......................................................................................................... 68 Exhibitors at Eurocombi3 ............................................................................................... 107 Delegate list .................................................................................................................... 113 Acknowledgements......................................................................................................... 117

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3rd EUROPEAN SYMPOSIUM ON COMBINATORIAL SCIENCES IN BIOLOGY, CHEMISTRY, CATALYSTS AND MATERIALS

by

The European Society of Combinatorial Sciences

Monday July 18th - Thursday July 21st 2005

University College Winchester, Winchester, U.K.

Organising Committee

Mark Bradley, Toby Cull, Phillip Milnes, Carole Brückler, Stifun Mittoo

International Scientific Committee

Mark Bradley, Andrea Basso, Stifun Mittoo, Oliver Kappe, Alasdair MacDonald Welcome to Eurocombi3, which is organised under the auspices of the European Society of Combinatorial Sciences (ESCS). The symposia in the past have been tremendously successful (Budapest 2001 and Copenhagen 2003) and have attracted in excess of 300 participants per event from all over the world. The program covers all aspects of HT and combinatorial science, including solid phase synthesis and reagents, materials science, medicinal sciences, peptide chemistry, organic and inorganic chemistry, and catalysis. It is our intention to make this a memorable event, both scientifically and socially. A large number of scientists are participating in this event and excellent speakers have accepted our invitation to present lectures. In addition to invited lectures, the program includes oral communications, poster sessions, a half-day young researcher symposium and major exhibition displays. We hope that this meeting will give a good opportunity to establish an inspiring atmosphere for the exchange of ideas. The Organising Committee

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Final Program

Sunday 17th July

Welcome Reception 18:30-20:00

Monday 18th July

8.00 Registration opens 9.00 - 9.10 Welcome and Opening of the Conference Professor Mark Bradley (Chairman of the Management Committee)

Morning Session 1: Libraries for Biological Effect Chair: Prof. Mark Bradley

9.10 -9.55 Focused Synthetic Libraries for the Efficient and Systematic Elucidation of Protease Function Professor Jonathan Ellman (University of Berkeley, California, U.S.A) 9.55-10.20 Cellulose-Supported High Throughput Chemical Synthesis and Biological Screening Dr Ronald Frank (German Research Centre for Biotechnology, Germany) 10.20-10.45 Fragment-based Library Design as a Means to Address Protein Function: Screening Selected Targets of Mycobacterium tuberculosis Professor Jörg Rademann (Leibniz Institute for Molecular Pharmacology, Germany) 10.45- 11.15 Coffee break and Exhibits

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Morning Session 2: Chemistry and Micro-arrays Chair: Dr Alasdair Macdonald

11.15-12.00 Automated Synthesis of Oligosaccharides: From Carbohydrate Arrays to Vaccines Professor Peter Seeberger (Swiss Federal Institute of Technology, Switzerland) 12.00-12.25 Chemical Microarrays. Platforms for Cell-based and High-Content Enzymatic Screenings Dr Juan Jose Diaz-Mochon (University of Edinburgh, UK) 12.25-12.50 A Novel Chemical Proteomics Platform using Immobilized Small Molecule Libraries to Investigate Cancer Cell-lines Dr Gyorgy Dorman (ComGenex Inc, Budapest, Hungary) 12.50-14.00 Lunch

Afternoon Session 1: HT Materials Research Chair: Prof. Helma Wennemers

14.00-14.45 High Throughput Physical Vapour Deposition Applied to the Synthesis and Primary Screening of Materials Professor Brian Hayden (University of Southampton, UK) 14.45-15.10 Combining DoE and HTE to Develop Amphiphilic Diblock Copolymers Dr Shian-Jy Wang (Industrial Technology Research Institute, Taiwan) 15.10 -15.35 Innovative Strategies for Fast Detection and Design of New Catalysts: Selected Examples for Carbon – Carbon Coupling Reactions Professor Olivier Lavastre (Centre for Innovation and Technologies, France) 15.35-16.00 The Discovery and Development of Stereospecific Propylene Polymerization Catalysts using High-Throughput Techniques Dr Vince Murphy (Symyx Technologies, CA, U.S.A.) 16.00-16.30 Coffee break, Exhibits and poster session

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Afternoon Session 2: MCR’s Chair: Prof. Oliver Kappe

16.30-16.55 Synthesis of a Novel Isonitrile Acid Labile Linker Polymer Supported and Applications in Multicomponent Condensations (MCCs) Dr Patrick Page (Serono Pharmaceutical Research Institute, Switzerland) 16.55-17.20 An Integrated Polymer-Assisted Toolbox for Multi-component Condensation Reactions Dr A Macdonald (Polymer Laboratories Ltd, UK) 17.20-17.45 Ugi Reactions with hydroxylamine derivatives Dr Andrea Basso (Università degli Studi di Genova, Italy) 17.45-18.05 New Reactions via Combinatorial Methods Dr Maxim Mironov (Urals State Technical University, Russia) 18.05 -19.30 Exhibition and Poster Viewing (Refreshments will be served) 20.00 Dinner

Tuesday 19th July

Morning Session 1: Microfluidics and HT Synthesis and Screening Chair: Dr György Dormán

8.45-9.00 Introduction to the ESCS Professor Morton Meldal (Carlsberg Laboratory, Denmark) 9.00-9.45 Micro-reactors for High Throughput Experimentation Professor Klavs Jensen (Massachusetts Institute of Technology, U.S.A.)

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9.45-10.10 Combinatorial experimentation for a fast track progress from discovery through to continuous manufacturing of new products Dr Thomas Schwalbe, (Microreactor Systems Provider Inc., U.S.A.) 10.10-10.35 Microwave Chemistry as a Platform for Drug Discovery Dr Jesus Alcazar (J&J Pharmaceutical Research and Development, Spain) 10.35 -11.05 Coffee break and Exhibits

Morning Session 2: Combinatorial Biology Chair: Dr Günther Jung

11.05-11.30 A combinatorial approach to optimise a prognostic test to follow-up Multiple Sclerosis disease activity Professor Anna Maria Papini (University of Florence, Italy) 11.30-11.55 A tale of two libraries: Using dual genetic libraries to find essential proteins and inhibitors of their function Professor Ernesto Abel-Santos (Albert Einstein College of Medicine, NY, U.S.A) 11.55-12.20 Solid-phase GPCR-screening of split mix non-peptide libraries. Fluorescent cells on beads. Professor Morten Meldal (Carlsberg Laboratory, Denmark) 12.20-12.45 Catalytic Peptide Dendrimers Professor Jean - Louis Reymond (University of Berne, Switzerland) 12.45-14.00 Lunch

Afternoon Session: Young Researcher Presentations – sponsored by the Chemical Computing Group

Chair: Dr. Stifun Mittoo 14.00-14.25 Diversity-oriented synthesis of bicyclic dipeptide mimetics and applications in combinatorial chemistry Dr Thomas Nielsen (Carlsberg Laboratory, Denmark)

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14.25-14.50 Quantitative Analytical Constructs for Building Blocks Reactivity Profiling Christophe Portal (University of Edinburgh, UK) 14.50-15.15 High - Medium - Low Throughput: An efficient optimisation methodology for new reactions Silvia Pereira (TU Delft, The Netherlands) 15.15-15.40 1,3,5-triazepan-2,6-dione as a novel peptide-derived scaffold for drug discovery: parallel synthesis, x-ray structures and first biological results Gersande Léna (Immunologie et Chimie Thérapeutiques, France) 15.40-16.10 Coffee break and Exhibits 16.10-16.35 Hydrophobically Assisted Switching Phase (HASP) synthesis: Parallel access to a library of highly amphiphilic glycolipids Jörg Bauer (Eberhard-Karls-University Tübingen, Germany) 16.35-17.00 Focused libraries as a starting point in diversity-oriented synthesis Federica Catti (University of St Andrews, UK) 17.00-17.25 Amino aldehydes in solid-phase combinatorial chemistry Frederik Diness (Carlsberg Laboratory, Denmark) 17.25-17.50 Esterolytic Receptors Bauke Albada (Utrecht University, The Netherlands) 18:00 Poster viewing and exhibition 20.00 Dinner

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Wednesday 20th July

Morning Session 1: Microwaves in HT Synthesis Chair: Dr Andrea Basso

9.00 – 9.45 2-Amino-6H-1,3-Thiazine Libraries via Solution and Solid-Phase Protocols Professor Oliver Kappe (Karl-Franzens-University Graz, Austria) 9.45 – 10.10 Fast and Versatile Peptide Macrocyclization Using Microwave Energy Professor Gerardo Byk (Bar Ilan University, Israel) 10.10 – 10.35 A Diversity-oriented, Microwave-assisted Synthesis and Decoration of the 2(1H)-pyrazinone Scaffold Professor Erik Van der Eycken (University of Leuven, Belgium) 10.35-11.00 Synthesis of Dihydropyrimidinone (DHPM) amide library by microwave-assisted combinatorial chemistry and high-throughput techniques Dr Bimbisar Desai, (Karl-Franzens-University Graz, Austria) 11.00 -11.30 Coffee break and Exhibits

Morning Session 2: Complex Library Synthesis Chair: TBA

11.30 -11.55 Solution- and solid-phase rapid synthesis for a library of bioactive natural product and its derivatives Professor Takashi Takahashi (Tokyo Institute of Technology, Japan) 11.55 – 12.20 Solid-supported synthesis of glycoconjugates Professor Harri Lönnberg (University of Turku, Finland) 12.20 -12.45 Multicore libraries through the use of oxidative fragmentation and core structure rearrangement protocols. Dr Nicholas Westwood (University of St Andrews, UK) 12.45 -14.00 Lunch

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Afternoon Session 1: Enabling Technologies and Informatics Chair: Dr Mike Davis

14.00-14.20 High Throughput Drug Discovery Dr Mythily Vimal (GlaxoSmithKline, UK) 14.20-14.40 The Use of HTE to allow Researchers to Innovate Paul Munton (Tessella Support Services plc., UK) 14.40-15.00 Recent advances in Microwave Assisted Organic Synthesis Dr Farah Mavandadi (Biotage, UK) 15.00-15.20 Integration of Microwave assisted chemistry into high throughput chemistry platform. Dr János Gerencsér (ComGenex Inc., Budapest) 15.20-15.40 Tools to enable Medicinal Chemist to explore the Hit to Lead process in parallel Dr Steve Jordan (Argonaut Technologies, UK) 15.40-16.00 Improving Compound Library Effectiveness with Efficient Storage Systems Dr Rhett Affleck (Discovery Partners International, U.S.A.) 16.00 Coffee will be available

Free time to visit and tour Winchester 19.30 Banquet Dinner (Guild Hall, Winchester)

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Thursday 21st July

Morning Session 1: Synthesis and screening of Combinatorial Libraries Chair: Dr Ronald Frank

9.00-9.45 Diversity-oriented synthesis of linear and cyclic peptidomimetic libraries with biological activity Professor Pierfausto Seneci (University of Milan, Italy) 9.45-10.10 Combinatorial approaches for screening superagonists and antagonists in T-cell-mediated and in innate immune responses Professor Günther Jung (University of Tübingen, Germany) 10.10-10.35 Synthesis of Library of Peptidoglycan Fragments for Elucidation of Their Action Mechanism in Immunostimulation Professor Yukari Fujimoto (Osaka University, Japan) 10.35-11.05 Coffee break and Exhibits

Morning Session 2: Supported Reagents Chair: Dr Alasdair MacDonald

11.05-11.30 A new, efficient coupling reagent for High-Throughput-Synthesis: Polymer-supported IIDQ Eric Valeur (Combinatorial Centre of Excellence, University of Edinburgh, UK) 11.30-11.55 The scope of polymer-supported Mukaiyama reagent for the preparation of solution-phase libraries Dr Stefano Crosignani (Serono Pharmaceutical Research Institute, Switzerland)

ESCS Publication Award winning talk Chair: Prof. Oliver Kappe

11.55-12.55 ESCS Publication Award Lecture: Tandem Lecture – HT-materials science, QCAR and materials modeling Professor Wilhelm Maier & Dr. Jens Scheidtmann (Universität des Saarlandes, Germany)

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12.55-14.00 Lunch

Afternoon Session: Peptide Based Catalysis Chair: Prof. Morton Meldal

14.00-14.45 Peptide-Based Diversity for Catalytic Asymmetric Reactions Professor Scott J. Miller (Boston College, U.S.A.) 14.45-15.10 Towards Solid Supported Combinatorial Libraries of Highly Selective Peptide Based Phosphine and Oxazoline Transition Metal Catalysts Dr Christian Christensen (Carlsberg Laboratory, Denmark) 15.10-15.35 Peptides as Asymmetric Catalysts for Aldol Reactions Professor Helma Wennemers (University of Basel, Switzerland) 15.40 Awards for Best Young Talks, Posters and Polymer Laboratories award 16.00 Conference End

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Invited speakers Professor Jonathan Ellman (University of Berkeley, California, U.S.A)

Biography: Professor, born 1962; B.S. Massachusetts Institute of Technology (1984); Ph.D. Harvard University (1989); NSF Postdoctoral Fellow, University of California, Berkeley (1992). Alfred P. Sloan Fellowship (1994-

1996); Eli Lilly Grantee Award (1994-1996); Office of Naval Research Young Investigator Award (1994-1997); Burroughs Wellcome Fund

1993 George Herbert Hitchings Award for Drug Design and Discovery (1993-1997); Arnold and Mabel Beckman Foundation Young Investigator Award (1993-1995); National Science Foundation Young Investigator Award (1993-1995); UC, Berkeley Department of Chemistry Teaching Award (1998); American Chemical Society Arthur C. Cope Scholar Award (2000); Society of Biomolecular Screening Achievement Award (2003); Scheele Award selected by the Swedish Academy of Pharmaceutical Sciences (2003).

Research Interests: Professor Ellman's group is focused on three major areas of chemistry development: (I) The development of robust, general and efficient methods for the asymmetric synthesis of amine-containing compounds. (II) The application of C-

H bond activation methods to the rapid construction of complex, bioactive structures. (III) The application of chemistry to systematically characterize biological systems to advance the treatment of disease.

Professor Brian Hayden (University of Southampton, UK)

Biography: Professor; Ph.D. University of Bristol through studies of adsorption, oxidation and exo-electron emission at metal and alloy surfaces (1979); Postdoctoral fellow at the Fritz Haber Institute of the Max Planck Society

developing surface sensitive optical spectroscopies for the investigation of adsorbed molecules (1979-1984); Lecturer at the University of Bath (1984-1988); Lecturer at the University of Southampton (1988); Senior lecturer (1990); Reader (1993); Personal chair (1995); Co-founder of the High Throughput University of Southampton ‘spin out’ company, Ilika Technologies (2004).

Research Interests: Research interests centre on surface science studies of metal and oxide single crystal surfaces with particular interests in dynamics, model heterogeneous and photo-catalysis, surface electrochemistry and electro-catalysis and

surface spectroscopies. Most recently he has extended research in model heterogeneous catalysis and electro-catalysis through the application of combinatorial methodologies and thin film materials growth

.

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Professor Klavs Jensen (Massachusetts Institute of Technology, U.S.A)

Biography: M.Sc. Technical University of Denmark (1976); Ph.D. University of Wisconsin (1980); Young Author's Award of the Electrochemical Society (1983); Presidential Young

Investigator Award (NSF) (1984); Camille and Henry Dreyfus Teacher-Scholar Award (1987); John Simon Guggenheim Fellowship (1987); Allan P. Colburn (1987), Charles M.A. Stine (1995), R. H. Wilhem (2000) Awards of the American Institute of Chemical Engineers; US National Academy of Engineering (2002), Fellow the Royal Society of Chemistry (2004).

Research Interests: Our research focuses on understanding and controlling the interaction of transport and reaction processes in the realization and testing of functional micro- and nano-structured materials and devices for chemical, optical, and electronic applications. We are exploring a wide range of microfabricated systems for chemical and biological applications with particular emphasis on systems for which microfabrication provides unique process advantages. We are also using physically based, detailed simulations of reactive systems, specifically simulation across

multiple length and time scales, to complement experimental studies and gain new insight into the underlying basic physical and chemical rate processes. We are engaged in synthesis and characterization of novel materials, including electroluminescent polymers, functional polymer coatings by chemical vapor deposition, and novel quantum dot composite materials, consisting of semiconductor clusters imbedded in a host material.

Professor C. Oliver Kappe (Karl-Franzens-University Graz, Austria)

Biography: Associate Professor, born 1965; Diploma degree (1989) & Doctoral degree (1992) in organic chemistry Karl-Franzens-University in Graz; Postdoctoral research work on reactive intermediates with Professor Curt Wentrup, University of

Queensland in Brisbane, Australia (1993-1994); Postdoctoral research work on synthetic methodology, alkaloid synthesis with Professor

Albert Padwa, Emory University in Atlanta, USA (1994-1996); Habilitation in organic chemistry, University of Graz (1996-1998); sabbatical at the Scripps Research Institute (La Jolla, USA) with Professor K. Barry Sharpless (2003) Dissertation Award of the Austrian Chemical Society (1993); Erwin-Schrödinger Fellowship of the Austrian Science Fund (1994); APART Fellowship from the Austrian Academy of Sciences (1996); Research Award of the Government of Styria (1998); Prous Science Award (2004).

Research Interests: The main research interest and expertise of the Kappe Group is in the area of microwave-assisted chemistry. Our labs are well equipped and over the years we have built up considerable knowledge in microwave-assisted organic

synthesis and related technologies. Other research areas persued in the group are solid phase synthesis, combinatorial chemistry and the preparation of bioactive heterocycles.

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Professor Scott J. Miller (Boston College, U.S.A.)

Biography: Ph.D. Harvard University (1994); NSF Postdoctoral Fellow, California Institute of Technology (1994-1996); Arthur C. Cope Scholar Award, American Chemical Society (2004); Pfizer Award

for Creativity in Organic Chemistry (2003); DuPont Young Professor Award (2000); Camille Dreyfus Teacher-Scholar Award (2000); Glaxo-Wellcome Chemistry Scholar Award (2000); Alfred P. Sloan Research Fellowship (2000); Cottrell Scholar Award of Research Corporation (1999); Eli Lilly Grantee (1999); NSF CAREER Award (1999).

Research Interests: Complex molecule synthesis is one of the key disciplines of modern chemical research. The development of new methods for the synthesis and derivatization of such structures is a multi-dimensional activity involving reaction design, development and application. Research in our group focuses on each of these aspects of chemical synthesis. Utilizing the architecture and design principles presented by biologically relevant structures and processes, we seek to discover new reactions and to apply new principles to the selective synthesis of complex molecules. As part of this program, we bring to

ear the full arsenal of modern synthetic b

chemistry. Employing organometallic chemistry, we are working to discover a series of new chemical transformations which enable the rapid synthesis of stereochemically complex structures. In addition, we are investigating the development of new catalysts for the selective functionalization of these molecules. A key component of our efforts is the determination of the fundamental molecular interactions which are responsible for reaction selectivities. As a result, a major focus of our research is an understanding of the inter- and intramolecular forces which allow selective chemical events to take place.

Professor Peter Seeberger (Swiss Federal Institute of Technology,

witzerland) S

Biography: Professor, born 1966; B.S. at the Universität Erlangen-Nürnberg as a Bavarian government fellow (1989); Ph.D. University of Colorado as Fulbright fellow (1995); Postdoctoral Fellow with S. Danishefsky at the Sloan-Kettering Institute for Cancer

Research in New York City (1997); Assistant Professor of Chemistry at the Massachusetts nstitute of Technology (1998-2002); Firmenich

Associate Professor of Chemistry, Massachusetts Institute of Technology (2002-2003); Professor for Organic Chemistry at the Swiss Federal Institute of Technology (ETH) Zurich, Switzerland and Affiliate Professor at the

I

Burnham Institute in La Jolla, CA (since 2003). Technology Review Top 100 Young Innovator Award (1999), Edgerton Award (2002), Arthur C. Cope Young Scholar Award from the American Chemical Society (2003), Horace B. Isbell Award from the American Chemical Society (2003), Otto-Klung Weberbank Prize (2004).

Research Interests: His research interests focus on the interface of chemistry and biology and in particular on the role of complex carbohydrates and glycoconjugates in information transfer in biological systems. His group has developed new methods for the automated solid-phase synthesis

of complex carbohydrates and glycosaminoglycans that serve as molecular tools. Other interests include synthetic methodology, total synthesis, immunology, and biochemical and biophysical studies of carbohydrates.

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Professor Pierfausto Seneci (University of Milan, Italy)

Biography: Laureato in Chimica Pura University of Milan; PhD University of Pavia; postdoctoral studies at the University of Milan with Professor C. Fuganti; in 1987 moved to Lepetit (Group of Marion Merrell Dow),

including an 18-month stay a the research centre in Strasbourg, France; in 1995 moved to Selectide Co., Tucson, U.S.A.; in 1996 transferred to the Medicinal chemistry Group of SmithKlineBeecham, Rennes, France; in 1997 took a directorship at the Department of Lead

Discovery, GlaxoWellcome, Verona, Italy; in 2000 founded a biotech company called Nucleotide Analog Design AG, Munich, Germany and served as Chief Scientific Officer, then as CEO; in 2003 moved to the University of Milan, Italy, as an Associate Professor while maintaining a consultancy role at NADAG; served as interim CEO of Sirenade from December 2003 through June 2004, when NADAG and Sireen merged, then assuming the CSO role. In May 2005 he joined as a consultant NiKem Research srl with the role of Chief Business Officer.

Research Interests: He has been involved in the synthesis of novel anti-inflammatory agents, in the drug discovery areas of antibacterial, antifungal, bone disease, cardiovascular, oncology and CNS drugs. He has acquired significant experience in natural products chemistry. He was involved in approaches to curing Alzheimer’s disease and

got interested in combinatorial chemistry and high throughput screening, leading to the synthesis and characterization of libraries of potential antibacterial and CNS agents. He is interested in natural products-like, diversity-based combinatorial libraries for medicinal purposes.

ESCS publication award winner Professor Wilhelm Maier (Universität des Saarlandes, Germany)

Biography: Ph.D., Philipps-University of Marburg (1978); Post-Doc, University of

Erlangen-Nürnberg (1979-1981); Assistant Professor, UC Berkeley, U.S.A. (1981-1988);

University Professor for Chemical Engineering, University (GH) of Essen (1988-1992); Max-Planck-Institut für Kohlenforschung and Professor at the University (GH) of Essen (1992-200); Chair for Chemical Engineering at the University of the Saarland (since 2000). Carl - Duisberg - Memorial Award (GDCh) (1993); Arnold - Lectureship at Southern Illinois University, Carbondale, USA (1996).

Research Interests: Our research interest is centered in the field of heterogeneous catalysis: preparation, property screening and application of catalysts. Our interest in research currently focuses on methods to discover and apply new materials and catalysts. We develop new methods in the field

of combinatorial chemistry to considerably accelerate the "primary screening" for new materials: robot-controlled synthesis, spatially resolved mass spectrometry, gas chromatography, IR-thermography and x-ray analysis.

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Monday 18th July 2005

Libraries for Biological Effect Focused Synthetic Libraries for the Efficient and Systematic Elucidation of Protease

Function

Jonathan A. Ellman1

1Department of Chemistry, University of California, Berkley, U.S.A. [email protected]

Proteases play an essential role in many biological processes and represent one of the most important classes of molecular targets for the development of therapeutic agents. However, the functions of most of the greater than 550 proteases encoded by the human genome have not yet been defined. A large number of additional proteases from other organisms, including pathogens, also require characterization. Systematic and efficient tools for deciphering protease function are clearly needed. Here, expedient nanodroplet-based microarray approaches to rapidly establish protease substrate specificity profiles will be described that have aided in the identification of physiological substrates and in the design of potent and selective inhibitors. A new, robust method to rapidly identify highly novel and completely nonpeptidic protease inhibitors, called substrate activity screening, will also be presented.

- 17 -


Cellulose-supported high throughput chemical synthesis and biological screening

Ronald Frank1

1Department of Chemical Biology, German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany

[email protected]

We have pioneered and continuously advanced the utilization of planar synthesis supports, cellulose membranes in particular, for the multi-step solid-phase assembly of chemical compounds by several types of special combinatorial and parallel synthesis techniques such as the Filter Disc Method (1983), the SPOT-synthesis (1990), and the Cut & Combine Method (1998). The planar, spatially addressable format of the membranes supports provides opportunities not easily available by e.g. beads, most prominently the synthesis without any reactor walls. Utilization of this type of support material in the further miniaturization, automation and integration of high throughput synthesis & biological screening processes for immunological, functional genomics, proteomics and drug discovery studies is an ongoing effort of the department. Special emphasis of the presentation will be put on recent achievements towards the assembly of combichem and natural product derived small molecule arrays fitted to their incorporation into a variety of different screening processes such as microarray-based binding assays and parallel continuous-format cell-based screening.

- 18 -


Fragment-based library design as a means to address protein function: screening selected targets of Mycobacterium tuberculosis

Jörg Rademann1,2

1Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rössle-Str. 10, 13125 Berlin, Germany; 2Institute for Chemistry, Free University of Berlin, Takustr. 3, 14195 Berlin, Germany.

[email protected] Nowadays, small organic molecule libraries contribute increasingly to the understanding of biological processes. New proteins are characterized structurally and functionally via their ligands or are identified through their interaction with small molecules. Therefore, the screening of small molecule libraries becomes an important tool also in academic research environments. Large libraries are costly to screen and still often yield disappointing hit rates. One alternative can be the use of small to medium-sized compound collections that are based on molecular entities of limited sized here named as fragments that serve as a starting point for structural variation, subsequent affinity optimization, or directly as a biological tool. We will discuss our recent contributions to the design and synthesis of fragment-based libraries and their use in primary and secondary screening. Focussed libraries have been prepared by novel solid-phase and polymer-supported methodology, namely C-nucleophilic linker reagents and hydrophobically-assisted switching of reaction phases (HASP-synthesis). Targets included various proteins from Mycobacterium tuberculosis, proteases and the innate immune response of human monocytes.

- 19 -


Chemistry and Micro-arrays Automated Synthesis of Oligosaccharides: From Carbohydrate Arrays to Vaccines

Peter H. Seeberger1,2

1Laboratory for Organic Chemistry, Swiss Federal Institute of Technology Zürich, Switzerland, 2The Burnham Institute, La Jolla, CA, U.S.A.

[email protected]

The importance of cell surface oligosaccharides and glycosaminoglycans in signal transduction processes of biomedical significance is now well established. A major impediment to the rapidly growing field of molecular glycobiology was the lack of pure, structurally defined carbohydrates and glycoconjugates. The application of an automated solid-phase oligosaccharide synthesizer we developed recently is described and applied to all classes of glycoconjugates. Based on the synthetic platform, a suite of tools for glycobiologists has been developed that includes carbohydrate arrays, fluorescently labeled oligosaccharides for imaging studies as well as affinity columns and other synthetic tools. Using the specific binding of certain bacteria to particular sugars was used to develop a visual detection system to test body fluids and water for the presence of pathogens including E. coli. To improve the detection of several pathogens at the same time, carbohydrate arrays were utilized to measure binding of cells to sugars. Described will be the development of carbohydrate based vaccines against a series of diseases including HIV, leishmania and tuberculosis. Particular emphasis will be placed on the example of an anti-toxin malaria vaccine that is currently in preclinical development.

- 20 -


Chemical Microarrays. Platforms for Cell-based and High-Content Enzymatic Screenings

Juan José Díaz-Mochón1, Mark Bradley1

1School of Chemistry, University of Edinburgh, West Mains Rd., Joseph Black Buildings, Edinburgh [email protected]

Microarray technology has been a crucial tool in the genomic era. However, its uses within the combichem field and in cell-based screenings are still in their early stages. Here the applications of this technology to both combinatorial libraries and cell-based assays are described. Split and mix libraries were tagged with PNA, allowing the complete interrogation of every member of the libraries using DNA microarrays to study substrate specificities of proteases and kinases. Novel 2D substrates containing polymer-based features were used as platforms to carry out cell-based assays which were analysed using an Automated Microscopy Imaging System. This methodology allows us to establish molecular targets using high-throughput techniques.

- 21 -


A novel chemical proteomics platform using immobilized small molecule libraries to investigate cancer cell-lines

György Dormán1, László G. Puskás2, László Hackler Jr.2, Zsolt Lőrincz3, Tamás Jankovics1, László Ürge1,

Ferenc Darvas1

1ComGenex Inc, H-1031 Budapest, Záhony u. 7; 2Laboratory of Functional Genomics, Biological Research Center, H-6726, Szeged, Temesvári krt. 62; 3ReComGenex Ltd, H-1031 Budapest, Záhony u. 7, Hungary

[email protected] Identification and selection of disease-specific targets is one of the most critical steps in post-genomic drug-discovery. Overexpression of genes and their protein products is often the best starting point for dissecting the pathways that lead to the development of specific diseases. Such proteins often serve as molecular targets particularly in cancer, where small molecules are designed to inhibit directly oncogenic proteins that are mutated and overexpressed. In our approach diverse small molecule microarrays are applied to identify such proteins directly from cell extracts/ fractions using healthy counterparts as controls. The advantage of this approach lies on the fact that the ‘positive’ small molecules can serve as a tool for target isolation and identification through affinity-based methods as well as for target validation using phenotypic assays. We present a case study on melanoma proteomics from the generation of microarrays to the in vitro phenotypic assays, where this approach was successfully applied.

- 22 -


HT Materials Research

High Throughput Physical Vapour Deposition Applied to the Synthesis and Primary Screening of Materials

Brian E.Hayden1

1School of Chemistry, University of Southampton, Southampton, SO17 1BJ [email protected]

A new method that combines the physical vapour deposition of pure elements from multiple finite size sources (e-beam and k-cell) in ultra high vacuum, with independently controlled source shutters has been optimised for the high throughput synthesis of material libraries. The source shutters are positioned to achieve a controlled gradient of the deposited element across the substrate, and is fixed during the course of deposition. Choice of the shutter position and the rate of deposition for each source allow the direct synthesis of continuous and controlled materials of varying composition. There are significant advantages of the method over alternatives which rely on sequential deposition and subsequent heat treatment to produce thin film materials. Combined with molecular or atomic gas sources, mixed oxides, hydrides and nitrides can also be synthesised, as can composite materials and supported particles. The thin film materials can be well characterised and well suited to primary screening either as continuous films or as masked fields on micro-fabricated screening arrays. Results are presented for the primary screening of fuel cell electrocatalysts where combination with secondary screens clearly provides a route to optimised materials. A new micro-hotplate chip for the primary screening of storage materials and catalysts using the masked PVD methodology will also be described.

- 23 -


Combining DoE and HTE to Develop Amphiphilic Diblock Copolymers

Shian-Jy (Jassy) Wang1, Harold Cheng1, Chia-Lin Liu1

1Industrial Technology Research Institute, Taiwan [email protected]

Amphiphilic diblock copolymers are widely used in as self assembly materials which will applied to optoelectronic or biopharmacutics industries. When the concentration of amphiphilic diblock copolymer in aqueous solution reached CMC (critical micelle concentration), they will form nanosize polymeric micelles and can be used to encapsulate hydrophobic molecules, such as drugs. In this paper, we demonstrated the parallel synthesis of amphiphilic diblock copolymers by using Design Expert 6 and Accelerator SLT106 synthesizer. After an amphiphilic diblock copolymer library was synthesised, samples were analyzed by NMR, MALDI-TOF-MS & GC which allowed us to build the data bank of amphiphilic diblock copolymers and polymeric micelles.

- 24 -


Innovative strategies for fast detection and design of new catalysts: selected examples for carbon-carbon coupling reactions

O. Lavastre,1 S. Garbacia, 1 L. Gallard, 1 R. Touzani,1 T. Regnier1

1Center for Innovation and Technologies Rennes, UMR 6509 CNRS Institut of Chemistry, University of Rennes 35042, France

[email protected]

A new approach for catalysts screening, based on image analysis of 2D chromatographies, will be reported. This method is able to give qualitative and quantitative informations of up to 48 catalysis in one shot. Detection of new catalysts for Sonogashira and Heck coupling reactions as well detection of unexpected reactions will be presented. Moreover in order to design new catalysts, it is necessary to develop new ligands or new strategies able to quickly generate libraries of ligands. Selected examples of multichelating ligands based on triazole or pyrazole and the impact of their synthesis under microwaves will be also discussed.

- 25 -


The discovery and development of stereospecific propylene polymerization catalysts using high-throughput techniques

T. Boussie,1 O. Brümmer,1 G. M. Diamond,1 A. M. LaPointe,1 M. K. Leclerc,1 . L. Micklatcher,1 J. A. W.

Shoemaker,1 V. Murphy,1 H. Turner1

Symyx Technologies, 3100 Central Expressway, Santa Clara, CA 95051, U.S.A. [email protected]

Symyx has pioneered the development of high-throughput techniques for the discovery and evaluation of olefin polymerization catalysts, and tools for the rapid characterization of associated polymer products. More recently, we have turned our attention to using these techniques for the discovery and development of new catalysts for the production of stereoregular polypropylene. This presentation will describe the use of diverse “discovery libraries” with multiple classes of ligands for initial catalyst discovery, followed by “focus libraries” through structural elaboration of the most promising “hit” ligand structures. High-throughput chemistries, analytics and stereospecific polypropylene catalyst discoveries will be presented.

- 26 -


MCR’s

Synthesis of a Novel Isonitrile Acid Labile Linker Polymer Supported and Applications in Multicomponent Condensations (MCCs)

Patrick Page1, Horacio Comas1, Thomas Moraux1

1Serono Pharmaceutical Research Institute, 1228 Plan-Les-Ouates, Geneva, Switzerland [email protected]

One of the key issues encountered in modern medicinal chemistry is the difficulty of discovering novel structures for various potential targets. This issue dramatically limits the opportunities for patenting molecules identified after primary screening. Nowadays, there is a strong need for new chemical entities (scaffolds) in the pharmaceutical industry. Diversity-directed thematic, and project driven libraries are often prepared using solid supports, testifying to the utility of this enabling technology to facilitate drug discovery. Similarly, multi-component condensations (MCCs) have also changed the landscape of organic and medicinal chemistry due to their ability to efficiently generate libraries of diverse compounds in one or two synthetic steps. In our continuing efforts to develop original approaches to access New Chemical Entities, we report the results of our investigations on novel synthetic technologies in solid-phase chemistry, particularly the development of a new Acid Labile Functionalised Isonitrile resin 1, its applications in multicomponent condensations, as well as its potential for new Tandem reaction processes (Scheme 1).

N

N

N

N+

N

OPol

C

N

R3

A N

NR2 R1

AN

NN

R1R4

R3

R21

Scheme 1

- 27 -


An Integrated Polymer-Assisted Toolbox for Multi-component Condensation Reactions

A A MacDonald2, P A Boguszewski1 , A F Coffey1, J W Davies1, A J Mendonca2, F P Warner1

1Polymer Laboratories Ltd, Essex Road, Church Stretton, Shropshire SY6 6AX, UK; 2Polymer Laboratories Inc, Amherst Fields Research Park, 160 Old Farm Road, Amherst MA 01002, U.S.A.

[email protected]

Multiple component condensation reactions (MCCRs) are highly attractive processes for parallel synthesis as libraries of compounds with drug-like structures and diverse substitution patterns can be synthesised in one step, often under mild reaction conditions. Herein we will describe an integrated polymer assisted approach to facilitate the synthesis and purification of multicomponent reactions. Polymer Laboratories have developed polymeric materials, which can be used to selectively scavenge functional groups across the whole spectrum of MCCRs. The effective use of these scavengers will be shown in the 3 and 4 component Ugi, Biginelli, Passerini and Petasis reactions. The utility of novel SPE materials that are well suited for the purification and free base generation of drug like libraries will also be described.

- 28 -


Ugi reactions with hydroxylamine derivatives

Andrea Basso,1 Luca Banfi,1 Giuseppe Guanti1and Renata Riva1

1Università degli Studi di Genova, Dipartimento di Chimica e Chimica Industriale, Via Dodecaneso 31, Genova, Italy

[email protected]

Multicomponent reactions (MCRs) are those condensations between three or more reactants, coming together in a single reaction vessel, forming a new product containing portions of all the components. They offer a number of advantages compared to traditional linear synthesis, such as selectivity, versatility, convergency and cleanliness; for these reasons MCRs are becoming increasingly popular in organic and medicinal chemistry. Although various novel multicomponent condensations have been recently discovered, the old Ugi MCR is still the most widely used. This isocyanide-based reaction is a very useful tool to prepare peptide-like molecules; in addition, other different pharmacologically relevant structures can be obtained when such a reaction is associated with post-condensation modifications or when non-classical building blocks are employed.

- 29 -


New Reactions via Combinatorial methods

Maxim A. Mironov, Sergey S. Maltsev, Maria I. Tokareva, Maria N. Ivantsova, Vasiliy A. Bakulev. Urals State Technical University, Department of Technology for Organic Synthesis, Russia

[email protected]

Combinatorial methods are widely used in various areas such as medicinal chemistry, catalysis and material science. Other, almost unexplored sphere of application is basic researches including search for new chemical reactions and synthetic ways. Recently, we have introduced a novel method for creation of new reactions, which consists in combinatorial replacements of reaction educts. This method allows us to transform well-known multi component condensations or oligomerizations into new, before undiscovered reactions. By analogy with function operator from mathematics we have proposed the term “reaction operator” for our methodology. We consider such strategy to be useful for development of the general concept of diversity-oriented synthesis. The scope and limitation of our approaches to creation of multi scaffold libraries will be discussed.

N COOMe

COOMe

COOMe

MeOOC

NN

R

RNC

CN

N

N

N

R S

R

NN

S S

R R

R N

R = Ar, Alk

- 30 -


Tuesday 19th July 2005

Microfluidics and HT Synthesis and Screening

Microreactors for High Throughput Experimentation

Klavs F. Jensen1

1Departments of Chemical Engineering and Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, U.S.A.

[email protected]

The microscale revolution in chemistry promises to transform classical batch wise laboratory procedures into integrated systems capable of providing new understanding of fundamental chemical processes as well as rapid, continuous discovery and development of new products with less use of resources and waste generation. New automated microreactor systems with multiple microreactors and integrated optical spectroscopy are presented. Applications of microreactors are illustrated with a broad range of case studies, including high throughput experimentation in organic synthesis (oligosaccharide synthesis), integration of ultraviolet (UV), visible and infrared (IR) spectroscopy for optimization of reaction conditions and extraction of chemical kinetics; investigations of multiphase reactions (e.g. ozonolysis, catalytic hydrogenation), enabling difficult to perform reactions (fluorination, high pressure reactions), and synthesis of colloidal silica nanoparticles and semiconductor quantum dots.

- 31 -


Combinatorial experimentation for a fast track progress from discovery through to continuous manufacturing of new products

Dr Thomas Schwalbe1

1MRSP – Microreactor Systems Provider, Inc., 84 Browne St., Brookline, MA 02446, U.S.A. [email protected]

Since the late 90s, a number of groups have been pioneering the concepts of continuous processing to the manufacture of fine chemicals in microreactors. The CYTOS® family of products cover the drug development pipeline space, they are well suited to take an optimised continuous process route from milligram to tens of tonnes scale. We report an integrated microreactor platform, the SEQUOS, and perform library synthesis and optimisations at a scale of mg to gram under identical chemical engineering conditions. A case study on the synthesis of a library of Ciprofloxacin analogues diversifies the core theme in two positions. The sequential synthesis of such compounds in a continuous regime grants favourable access to higher quantities of diversified building blocks in discovery. A Grignard reaction case study reveals process sensitivity by sequential experimental investigation. It allows an economical decision for a continuous manufacturing plant, or provides optimisation kinetic data for deployment in a batch plant. References to Cytos plants and their economic layout shall be mentioned.

- 32 -


Microwave Chemistry as a Platform for Drug Discovery

Jesús Alcázar1

1Johnson & Johnson Pharmaceutical Research and Development, Division of Janssen-Cilag, S.A. Jarama s/n. 45007 Toledo, Spain

Microwave chemistry has emerged as the most efficient way of heating reactions, because the heating is instantaneous and rapid. As a result reaction times are shortened and higher yields of product are obtained. These advantages can be used to speed up the synthesis of compounds in drug discovery programs. Some authors have claimed that microwaves will be the heating source of the future. In order to get the maximum profit of microwave technology an appropriate platform should be built. This platform should fit as much as possible all the situations that can be found in the drug discovery process. For instance: reaction optimization, scale up or parallel chemistry. An interesting approach of microwave chemistry as a platform for drug discovery is the combination of single-mode and multimode instrumentation. Unfortunately this approach has only been recently validated for the scale up of single compounds. Full validation of this combined platform, including parallel scale up and reactions in multi-well plates, as a way to speed up the synthesis of compounds in drug discovery programs will be presented.

- 33 -


Combinatorial Biology

A combinatorial approach to optimise a prognostic test to follow-up multiple sclerosis disease activity

Anna Maria Papini1, M.C. Alcaro1, E. Peroni1, B. Mulinacci1, A. Carotenuto2, G. Sabatino1, B. Mazzanti1,

M. Pazzagli1, M.C. Pozo-Carrero1, F. Nuti1, L. Battistini3, M. Chelli1, F. Lolli1, P. Rovero1

1Laboratory of Peptide & Protein Chemistry & Biology, Polo Scientifico of the University of Florence, Sesto Fiorentino, Italy; 2Department of Pharmaceutical and Toxicological Chemistry, University of Naples "Federico II", Napoli, Italy; 3Istituto di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia,

Neuroimmunology Unit, Rome, Italy

From a structure-based design, we developed the first generation of antigenic glycopeptide probes to detect sugar-specific autoantibodies, correlating with disease activity of a consistent population of Multiple Sclerosis (MS) patients. CSF114(Glc) displayed a well-defined conformational preference in solution, characterized by a β-hairpin motif with the sugar moiety on the tip of a type I’ β-turn structure. By a combinatorial approach, after defining the role of the sugar moiety and of the peptide conformation, we precisely defined the minimal epitope fundamental for autoantibody recognition. The second generation of CSF114(Glc) probes was selected to develop the first prognostic test (produced by the spin-off of the University of Florence EspiKem Srl and commercially available by CSF Srl) to detect specific biomarkers of MS. An extensive validation study on MS patients followed longitudinally in comparison to blood donors and patients affected by other autoimmune diseases demonstrated the reliability of the approach.

- 34 -


A tale of two libraries: Using dual genetic libraries to find essential proteins and inhibitors of their function

Lisa Nilsson1, Mostafa Louassini1, and Ernesto Abel-Santos1

1Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, U.S.A.

[email protected]

We developed a dual library system to query for protein function in vivo while simultaneously finding inhibitors of their biological activity. The first library consists of genetically encoded cyclic peptides (SICLOPPS) that knock-down metabolic pathways, thus causing phenotypic changes in the host cells. The second library consists of genomic fragments and is used to screen for gene products targeted by peptide inhibition. As proof of principle, a SICLOPPS library was introduced into Escherichia coli cells. SICLOPPS library over-expression afforded six distinct bacteriostatic peptides. One of these peptides (LN05) also caused cell aggregation. An E. coli genomic library was introduced into cells encoding LN05. Genomic library and LN05 co-expression resulted in enrichment of a single genomic construct, a fragment of the NarZ gene, which counteracted peptide toxicity. NarZ is part of a nitrate reductase complex and has a role in tuberculosis persistence. LN05 production in Mycobacteria resulted in a slow-growth phenotype.

- 35 -


Solid-phase GPCR-screening of split mix non-peptide libraries. Fluorescent cells on beads

Morten Meldal1, Thomas E. Nielsen1, Frederik Diness1, Ole Thastrup2, Grith Hagel2

1Carlsberg Laboratory, SPOCC Centre and 2Carlsberg Biosector, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark

[email protected]

GPCR’s are amongst the most valuable targets in pharmaceutical industry, but have failed to provide nano-scale assays of combinatorial compound libraries due to their functional complexity and nature as membrane bound proteins. The development of true biocompatible resins for library synthesis has facilitated whole cell assays on beads by a” two compounds one bead” method in which an adhesion molecule and a library of receptor activators are attached to the same bead. By coupling receptor activation to expression of YFP high speed FABS sorting and automation was feasible. From new libraries of receptor relevant molecules obtained through quantitative cascade reactions involving aldehyde condensation with backbone amide and reaction of intermediate N-acyliminium ions with C, N, O and S nucleophiles on solid support to form non-peptidic small molecules from small peptides. The structure hits for the MCR4 receptor were elucidated from single beads using LCMS/MS for resynthesis and solution assay.

- 36 -


Catalytic Peptide Dendrimers

Jean-Louis Reymond1

1University of Berne, Freiestrasse 3, CH-3012 Berne, Switzerland

In de novo protein design one attempts to create artificial proteins with defined structure and function from first principles, usually with the help of trial-and-error procedures that scan a large number of possible amino acid sequences. Our approach to de novo protein design is based on peptide dendrimers. Dendrimers are tree-like structures that adopt a globular or disk-shaped structure as a consequence of topology rather than folding. Our peptide dendrimers are obtained by alternating alpha-aminoacids with branching diaminoacids. Dendrimers containing combinations of histidine, serine and aspartate display enzyme-like catalytic properties for the hydrolysis of esters, including enantiomeric discrimination. The catalytic effect involves cooperative substrate binding and catalysis by a positive dendritic effect. We have now developed a combinatorial approach enabling the preparation of libraries containing over 60’000 different peptide dendrimers. A protocol was established for screening the beads for catalytic turnover and determining the dendrimer sequence on single resin beads. Screening of a combinatorial peptide dendrimer library leads to peptide dendrimers with esterase activity. The library approach was also used to discover peptide dendrimers with binding affinity to ligands. Peptide dendrimer libraries provide a new and versatile source of artificial proteins acting as functional supramolecular systems for molecular recognition and chemical catalysis. Recent data relating to the selection and properties of enantioselective catalytic peptide dendrimers and ligand-binding dendrimers will be discussed.

Figure 1 CPK-model of an esterase peptide dendrimer.

- 37 -


Young Researcher Presentations – sponsored by the Chemical Computing Group

Diversity-oriented synthesis of bicyclic dipeptide mimetics and applications in combinatorial chemistry

Thomas E. Nielsen1 and Morten Meldal1

1Carlsberg Laboratory, SPOCC Centre, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark [email protected]

To meet the challenge of generating structural analogs of bioactive peptides with enhanced therapeutic properties, combinatorial libraries of peptides incorporating conformational constraints have been widely investigated. Taking advantage of intramolecular condensation reactions of peptide aldehydes with the amide backbone, generating synthetically versatile cyclic 1-acyliminium ions, a unique route allowing the solid-phase assembly of structurally diverse bicyclic dipeptide mimetics has been designed. The course of the reaction sequence is strictly dictated by the side-chain of the amino acid neighbouring the 1-acyliminium intermediate. Miscellaneously substituted aromatic side-chains (aryl, heteroaryl) give rise to tetrahydro-carbolines, tetrahydroisoquinolines and related scaffolds via Pictet-Spengler cyclization. Side-chains containing heteroatomic moieties (-NH2, -CONH2, -SH, -OH) provide aza-, thia-, and oxabicyclic lactams, whereas aliphatic side-chains force the amide backbone to undergo a second cyclization reaction, thus affording bicyclic bis-lactams. The quantitative nature of these cascade processes renders the methodology well-suited for the synthesis of diverse combinatorial libraries.

- 38 -


Quantitative Analytical Constructs for Building Blocks Reactivity Profiling

Christophe Portal1, Mark Bradley1

1School of Chemistry, University of Edinburgh, Joseph Black Building, Edinburgh, EH9 3JJ [email protected]

A polymer supported analytical construct was used to quantify the reactivity of a range of monomers in the Ugi reaction, using positive electrospray mass spectrometry. To the resin was attached a lysine residue one arm of which provided an amine function necessary for the reaction and on the other was attached an analytical enhancer. The latter incorporated a bromine atom to act as a peak splitter and a quaternary ammonium to act as a mass spectrometry sensitizer and ionisation leveller to allow quantitative analysis of the cleaved construct by positive electrospray mass spectrometry. The reactivity of ten carboxylic acids was quantified due to the relative amounts of product they generated. Isocyanides and aldehydes were also investigated in the same way. The effect of the quantity of monomers on the reactivity and the conversion of the reaction was also investigated. A solution phase version of the construct was also investigated.

- 39 -


High - Medium - Low Throughput: An efficient optimisation methodology for new reactions

Silvia R. M. Pereira1, Lars Veum1, Ulf Handefeld1 and J. C. van der Waal1,2

1Laboratory for Applied Organic Chemistry and Catalysis, TU Delft, 2Avantium Technologies B.V.

The successful developments of High Throughput (HT) parallel synthesis and screening methodologies has accelerated research and improved its reproducibility and accuracy. The introduction of HT into the chemistry lab has emphasized the need for new research methodologies and data analysis techniques. Statistical algorithms (e.g. Genetic Algorithms, Simulated Annealing) and other Chemometric tools (e.g. Experimental Design) provide an efficient way to achieve the full potential of HT. The reduction of acylated cyanohydrins (see Scheme) is of particular interest. The products obtained are potential intermediates for various pharmaceuticals, such as ß-blockers. Here we report an efficient way of planning the experiments by using Experimental Design strategies, specific for each stage in the research, thus tuning the reaction conditions towards high yields. The rational method applied proved to be highly time and knowledge efficient. The identified hits found in the screening stages were successfully scaled-up and further optimised in conventional autoclaves. A highly selective catalytic system was identified, and yields above 80% were obtained.

R

O R'

O

CN

?

R

OHN R'

O

H

H2

- 40 -


1,3,5-triazepan-2,6-dione as a novel peptide-derived scaffold for drug discovery: parallel synthesis, x-ray structures and first biological results.

Gersande Léna1, Pascal Muller 2, Jean-Paul Briand1, Didier Rognan2, Gilles Guichard1

1Immunologie et Chimie Thérapeutiques UPR 9021 CNRS, IBMC, 15 rue Descartes, 67084 Strasbourg, France;2Laboratoire de Pharmacochimie de la Communication Cellulaire UMR CNRS-ULP 7081, 74 route

du Rhin, BP 24, 67401 Illkirch, France [email protected]

The design and synthesis by combinatorial chemistry techniques of cyclic/polycyclic frameworks that can efficiently distribute selected pharmacophores in the 3D space is an important method in the search for small-molecules capable of modulating biological processes. Our interest in designing and evaluating scaffold (I) stemmed from the remarkable biological activities exhibited by molecules with diazepine and triazepine skeletons including seven-membered cyclic ureas. 1,3,5-triazepane-2,6-dione (I) is a previously unreported densely functionalised peptide-derived structure which offers up to 5 sites of diversity readily varied from α-amino acids and displayed in a constrained orientation. 1,3,5-triazepan-2,6-diones are synthesized in solution in only four steps by cyclization of simple, activated dipeptide precursors. In order to generate prospecting or focussed libraries, a solid-supported synthesis utilizing the “catch and release” strategy was developed. In addition, interesting structural features as well as preliminary biological screening of the library, assisted by computational chemistry will also be discussed in this communication.

N

N

N

OR1R5

R2

OR3

R4 * *

I

- 41 -


Hydrophobically Assisted Switching Phase (HASP) synthesis: Parallel access to a library of highly amphiphilic glycolipids

Jörg Bauer1,2 and Jörg Rademann2,3

1Institute for Organic Chemistry, Eberhard-Karls-University Tübingen, 72076 Tübingen, Germany 2Leibniz Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany

3Institute for Chemistry, Organic Chemistry, Free University of Berlin, 14195 Berlin, Germany [email protected]

Rhamnolipids were found to induce immune response by release of cytokines. For structure-activity studies of the immune modulation, the parallel preparation of glycolipids had to be developed allowing for the efficient and high yielding variation of the lipid and carbohydrate parts. We will present the synthesis of a focused library of highly amphiphilic rhamnolipids employing Hydrophobically Assisted Switching Phase (HASP) synthesis. HASP-synthesis is our new concept which allows the choice between the advantages of solid-supported chemistry and those of solution-phase synthesis. It proved to be of exceptional value for the preparation of oligosaccharides overcoming several of the limitations encountered in solid-phase-synthesis of glycoconjugates so far and can evidently be extended to general organic synthesis. In addition to the HASP-synthesis of the complex rhamnolipid-library, immunological and biophysical data from the characterization of the compounds will be presented.

- 42 -


Focused libraries as a starting point in diversity-oriented synthesis

Federica Catti1, Kimberly Carey2, Jeralyn D. Haraldsen2, Gary E. Ward2, Nicholas J. Westwood1*

1BMS Building, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST; 2Department of Microbiology and Molecular Genetics, 316 Stafford Hall, University of Vermont, 95

Carrigan Drive, Burlington VT 05405, USA [email protected]

Toxoplasma gondii is an important water- or food-borne pathogen that is capable of causing severe disease in immuno-compromised patients. This chemical genetic project aims to use synthetic chemistry to increase our understanding of host cell invasion by Toxoplasma gondii. It also focuses on our efforts to improve potency and selectivity within a particular compound class. A phenotype-based high-throughput screen of 12,160 structurally diverse small molecules identified 24 noncytotoxic inhibitors of Toxoplasma invasion. For inhibitor 1 a synthetic procedure compatible with automated synthesis equipment has been developed and optimised. This procedure was used for the high-throughput synthesis of a library of 96 analogues of this inhibitor. Biological analysis of our compound array identified inhibitors with an increased activity and a useful S.A.R. series. In addition to their relevance to parasite invasion mechanisms, we also view our collection of 96 analogues as a potential starting point for the development of a diversity-oriented library. In this presentation we will report our results towards this goal including an interesting Diels-Alder ring fragmentation sequence to access compounds of type 2.

N

NO

O

2

R

OR' R'

1: R=N-propyl, R'=p-F

- 43 -


Amino aldehydes in solid-phase combinatorial chemistry

Frederik Diness1 and Morten Meldal1

1SPOCC-center, Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark [email protected]

Two of the most important themes in solid-phase combinatorial chemistry are product purity and diversity. In this light, amino aldehydes represent an interesting type of compounds due to their easy accessibility from the diverse pool of amino acids and to their bis-functional nature, which opens up for a wide range of high-yielding amine and aldehyde chemistry. However, handling amino aldehydes in solution and on solid support is a delicate task due to their tendency to self-condensate and epimerize. This has called for new methods for protecting/masking the reactive aldehyde functionality. We here present methods for synthesising building blocks based on protected amino aldehydes and their application in a range of solid-phase reactions with near quantitative formation of product. These include among others intramolecular Pictet-Spengler reaction, imidazolidinone synthesis and synthesis of various cyclic acetals. Further functionalisation of the generated tetrahydro-carbolines, tetrahydro-isoquinolines and imidazolidinones and synthesis of combinatorial libraries are also presented.

- 44 -


Esterolytic Receptors

H. Bauke Albada1, Rob M.J. Liskamp1

1Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, NL-3508 TB Utrecht, The Netherlands

[email protected]

Artificial receptors, capable of selective and strong binding, have received a lot of attention. The next challenge is to develop synthetic receptors possessing catalytic activity. In this approach, an orthogonally protected triazacyclophane (TAC) scaffold was used to construct synthetic receptors consisting of three different peptidic arms, each containing different sets of amino acids. For the sets acidic (Asp, Glu), basic (His, Lys) and nucleophilic (Ser, Cys) amino acids were chosen, since these are found in active sites of hydrolytic enzymes. Furthermore, electrostatic interactions of charged N-termini were blocked by trifluoroacetylation. By the split-mix method a library of 19,683 members was prepared. Screening of this library with latent fluorescent substrates allowed identification of esterolytic receptors. Sequence analysis of the receptors showed a high degree of functional amino acids, together with a few hydrophobic amino acid residues. Although many synthetic receptors contain catalytic triad combinations, apparently only a few showed activity.

- 45 -


Wednesday 20th July 2005

Microwaves in HT Synthesis

2-Amino-6H-1,3-Thiazine Libraries via Solution and Solid-Phase Protocols

C. Oliver Kappe Institute of Chemistry, Karl-Franzens-University Graz, Austria

[email protected]

In the last decade a considerable amount of attention has focused on multicomponent condensation reactions (MCRs) of the Biginelli type. The heterocyclic pyrimidine derivatives 1 (DHPMs) derived from the acid-catalyzed condensation of a ß-ketoester, aldehyde and (thio)urea building block (Biginelli condensation) represent privileged scaffolds with remarkable pharmacological properties. In this lecture we describe the generation of related 1,3-thiazine scaffolds of type 2 that can be considered as isomers of the classical Biginelli dihydropyrimidines 1 (X = S). Since the basic 2-amino-1,3-thiazine ring system is expected to have very different physicochemical, pharmacological and pharmacokinetic properties compared to the cyclic (thio)urea structures 1 we became interested in developing protocols for the automated synthesis of thiazine libraries 2, allowing for maximum flexibility and diversity (R1-R4) in the approach. Toward this end we have developed both a solution-phase and a solid-phase method for the synthesis of 2-amino-1,3-thiazines that employs a sequential combination of ß-ketoester, aldehyde and thiourea building blocks.

N

S

R2 NH

R1O

R3R4

2

N

NH

R2 X

R1O

R3

1; X = O, SR4

- 46 -


Fast and Versatile Peptide Macrocyclization Using Microwave Energy

Gerardo Byk,1 Damian Visnovetsky1 and Daniel Raichman1

1Bar Ilan University, Department of Chemistry, Laboratory of Peptidomimetics and Genetic Chemistry, 52900-Ramat Gan, Israel

[email protected]

Macrocyclization has been applied for two decades to improve the pharmacokinetic profile and biological activity of peptides. Macrocyclization brings about improved bioavailability and selectivity towards specific biological targets. The Heck metathesis on peptides, was used during the last decade for introducing macrocyclization into peptides. This reaction proceeds at high temperatures and is time consuming giving low yields. Larhead and others, have demonstrated the fast microwave mediated intermolecular Heck metathesis and in some examples intramolecular in small molecules. In this work we have investigated the intramolecular Heck metathesis using ring-varying peptides and peptoids and applied the synthesis to parallel solid supported synthesis using the tea-bag method. We demonstrate that the intramolecular Heck metathesis can be performed in peptides using microwave energy within 2 to 10 minutes in DMF solutions with yields ranging from 25 to 50 % (purified products). These results make the Heck Metathesis an attractive renewed approach for peptidomimetics.

- 47 -


A diversity-oriented, microwave-assisted synthesis and decoration of the 2(1H)-Pyrazinone scaffold

Erik Van der Eycken1

1Laboratory for Organic Synthesis, Department of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium

[email protected]

The 2(1H)-pyrazinone scaffold can allow the easy introduction of a wide range of pharmacologically active groups with the ability to address the diverse set of biological targets. Therefore this scaffold could be regarded as an interesting new type of “privileged structure”. We will comment on the application of microwave irradiation for the performance of a diverse set of reactions in solution phase, i.e. via “Click Chemistry” (Scheme 1), paving the way for the generation of small combinatorial libraries. Furthermore, we will describe the first (microwave-assisted) synthesis of the 2(1H)-pyrazinone scaffold on solid support and the consecutive application of microwave-irradiation to perform hetero-Diels-Alder reactions as well as transition metal-catalyzed reactions (see Scheme 2) for the further decoration of this scaffold.

Scheme 1: Scheme 2:

N

N O

ClCl

Ph

N

N O

PhCl

Ph

N

N O

R3Cl

Ph

N

N O

NHCl

Ph

N

HN O

PhCl

Ph

R3 = PhN

HN O

Cl

Ph

N

N O

NHCl

Ph

R3

OH

Suzuki, MW

Stille, MW

Ullman, MW

Sonogashira, MWMW

MW

OMe OMe

direct construction on the resin

OAcO

AcO NNN

N

NO

Cl

R1

R6

N

N O

Cl

R6

R1

OAcO

OAcO

X OAc

OAcO

AcO

OAcN

Y NN

N

NO R1

R6

Cl

- 48 -


Synthesis of Dihydropyrimidinone (DHPM) amide library by microwave-assisted combinatorial chemistry and high-throughput techniques

Bimbisar Desai,1 C. Oliver Kappe1 and Daryl Sauer2

1Institute of Organic & Bioorganic Chemistry, Karl-Franzens- University Graz, Heinrichstrasse 28, A-8010 Graz, Austria, 2High-Throughput Organic Synthesis Group, Abbott Laboratories, D-R4CP, AP-9B, 100

Abbott Park Road, Abbott Park, IL 60064-6113, U.S.A. [email protected]

Microwave-assisted organic synthesis (MAOS), combinatorial chemistry and high-throughput techniques are instrumental in rapid synthesis, screening and identification of compounds with new and improved biological activities. A set of multifunctionalized dihydropyrimidinones (DHPMs) 4 viz. the Biginelli scaffold (10 members) have been generated using controlled microwave heating as a representative of structurally diverse precursors to derive them into a corresponding set of the DHPM carboxylic acids 5. Efforts to generate the DHPM acid moieties also involve a continuous flow hydrogenation protocol for deprotection studies on selected starting DHPMs. An automated microwave-assisted high speed combinatorial library synthesis of the DHPM C-5 amides 6 (ca. 400 members) utilizing the above set of DHPM acids (10 members), a set of diverse amines (48 members) and their high throughput purification has been studied.

N

NH

R4 X

N

OR5

R6

R1

R2

N

NH

R4 X

O

R1

HO

R2

N

NH

R4 X

O

R1

OR3

R2

OR4

HO

R2

NH2

XHNR1

amide synthesis

C-5 esterO-deprotection

Biginellicondensation

1

23

4

56

O

OR3

+

R3 = benzyl or allyl

- 49 -


Complex Library Synthesis Solution- and solid-phase rapid synthesis for a library of bioactive natural product

and its derivatives

Takashi Takahashi1

1Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan [email protected]

A combinatorial library synthesis of macrosphelide and its analogues will be presented. Toward a high-speed synthesis of macrosphelide analogues, the efficient method for coupling of the three synthetic building blocks on solid-phase was developed. The process involves: (i) attachment of the secondary alcohol in block A to a polymer-support, (ii) esterfication with block B, (iii) palladium-catalyzed chemoselective carbonylative esterification of the vinyl iodide in unit A with block C containing a vinyl bromide moiety, (iv) palladium-catalyzed carbonylative macrolactonization, (v) cleavage from the polymer-support and removal of the protecting groups. As a result, the synthesis of 122-member natural product like library was accomplished.

OO

O

O

O

O

HO

OH

macrosphelide A

HO

BrAO

OR

I

HO

O

HO OR

C

B

Pd, CO

Pd, CO

(i), (v)

(ii)

(iii)

(iv)

- 50 -


Solid-supported synthesis of glycoconjugates

Johanna Katajisto,1 Pasi Virta,1 Petri Heinonen,1 Marika Leppänen1 and Harri Lönnberg1

1Department of Chemistry, University of Turku, FIN-20014 Turku, Finland [email protected]

Recognition of cell surface lectins by glycoclusters that allow multipoint interaction through several sugar ligands has received increasing interest as a potential method to provide oligonucleotides, peptides or small molecule drugs with cell type specificity. Accordingly, solid-supported methods for synthesis of combinatorial libraries of various types of multiantennary glycoconjugates have recently been under active development. We now describe several novel protocols for preparation of glycoconjugates of oligonucleotides and peptides, as well as for synthesis of cyclic hybrids of sugars and amino acids. The essential features of these procedures include exploitation of orthogonally protected multipodal scaffolds and solid-supported cyclization, oximation and carbamate coupling, in addition to the coupling methods conventionally used in oligonucleotide and peptide synthesis.

- 51 -


Multicore libraries through the use of oxidative fragmentation and core structure rearrangement protocols

Nicholas J. Westwood1

1School of Chemistry and EastChem, University of St Andrews, St Andrews, Fife, UK, KY16 9ST

Short, efficient chemical sequences that rapidly build diverse chemical structures drive high-throughput synthesis. Our group is focussed on the development of sequences of this type. In one recent approach, we have used an oxidative fragmentation reaction carried out on readily accessible pentacycles1 as a means of accessing libraries of small molecules containing medium-sized rings. In a subsequent chemical step, the incorporation of a diverse range of nucleophiles is achieved with concomitant rearrangement of the core structure. This sequence, therefore, enables us to access examples of three significantly different core structures in three chemical steps. Chemical validation studies of each step in the sequence will be presented coupled with the results of automated parallel synthesis studies carried out by the author during a recent EPSRC-funded Industrial Secondment in HT synthesis.

- 52 -


Enabling Technologies and Informatics

High throughput Drug Discovery

Mythily Vimal11

1GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW [email protected]

The pharmaceutical industry has come under increasing pressure to deliver new medicines and speed up the drug discovery process. After initial high expectations high throughput chemistry has matured to provide a new paradigm for drug discovery. The development of new technologies and the advent of polymer bound reagents mean thousands of compounds can now be prepared using both solid and solution phase technologies in the time taken to prepare just a few by conventional methods. The presentation will focus on automation and technologies used at GSK to achieve efficient production and purification as well as the importance of integrating the many components of this complex process. Particular emphasis will be made on the development of an efficient solution phase strategy using block synthesis and GSK chemistry resources for the production of arrays. This process has been a good source of screening hits and leads for medicinal chemistry targets.

- 53 -


The Use of HTE to allow Researchers to Innovate

Paul MuntonTessella Support Services plc. 3 Vineyard Chambers, Abingdon, Oxfordshire, OX14 3PX

[email protected]

The introduction of High Throughput Experimentation to a business can be a complex and challenging task. In particular, the impact of IT systems used to assist researchers through the HTE process, collect and manage the data can determine the success or failure of HTE. A world leading consumer products company has been in the process of introducing HTE for its research and needed a data management solution with more flexibility that a traditional LIMS. The Experiment Management System (EMS) is a web-based solution that concentrates around the experiment rather than the sample. The system pushes the boundaries of the web application by providing functionality that is more commonly associated with ‘thick clients’; for example, the drag and drop of formulations onto a visual representation of a microtitre plate. The system is designed for flexibility and allows experiments to vary from the ideal (assay defaults) and also allows researchers to use placeholders for materials/formulations during an experiment and cross reference them at a later date. This presentation will discuss the key challenges, both technical and cultural, of High Throughput Experimentation, as well as possible solutions.

- 54 -


Recent advances in Microwave Assisted Organic Synthesis

Farah Mavandadi1

1Biotage Ltd, 15 Harforde Court, Foxholes Business Park, Hertford [email protected]

As precise control of reaction conditions encourages medicinal chemists to include microwave technology as a standard tool in organic chemistry laboratories, technological advances in microwave-assisted organic synthesis (MAOS) continue to grow. Combining productivity enhancing tools such as microwave synthesis and high-performance flash chromatography significantly speed up the drug development process. This talk will address the recent advances in combining the MAOS with other cutting edge techniques for rapid production of organic compound libraries.

- 55 -


Integration of Microwave assisted chemistry into high throughput chemistry platform

János Gerencsér1, Tamás Szommer1, András Lukács1, György Dormán1, László Ürge1 and Ferenc Darvas1

1ComGenex Inc., H-1031 Budapest, Záhony u. 7., Hungary [email protected]

The application of Microwave-assisted chemistry opened new avenues in organic synthesis. However, microwave (MW) techniques did not significantly penetrate the high- throughput chemistry field so far. Over the past few years we integrated new methodologies including MW and microfluidics-based methods into our high-throughput synthetic platform, ComGenex Matrix Technology (CMT). This included the implementation of instruments and the design and creation of a microwave-based reaction database. The implementation of the MW systems has resulted in significant improvement in several aspects including the extension of the number of chemical reactions used, increased success rate, real time chemistry and productivity. In our talk we present specific examples of such multi-level integrated production lines where MW is linked with microfluidic tools (e.g. for continuous flow hydrogenation) and classical techniques. In the presentation we will discuss new and improved chemistries compared to conventional methods that resulted in novel structures in our medicinal chemistry programs.

Y X

R1n

N

O

R2

R3

N

N

S

R1

R2

R3

NR4R5

N N

R3

R1

R2NHR4

NH

NR2

R4

XR1

O

OR3

NAr1 N

Ar2

R1

R2

X= N, O, SY= O, S, N

X= O, S

- 56 -


Tools to enable Medicinal Chemist to explore the Hit to Lead process in parallel

Steve Jordan1

1Argonaut Technologies, Dyffryn Business Park, Ystrad Mynach, Hengoed, Mid Glamorgan, CF82 7RJ [email protected]

There have been advances in High Throughput Screening and Combinatorial Chemistry in the last few years, but the number of compounds reaching the market has fallen steadily. Whilst the quality of hits from the screens is reported to be improving we still need the ability to process these quickly and identify candidates worthy of progression through to lead optimisation. The focus of hit to lead is to provide data around a series of compounds that allows a rapid decision to be made on whether to progress the compound or not. This talk will focus on enabling tools for the medicinal chemist to expedite this process.

- 57 -


Improving Compound Library Effectiveness with Efficient Storage Systems

Dr. Rhett Affleck1

1Discovery Partners International, U.S.A. [email protected]

Compound management systems make compromises in storage conditions and have limitations in compound access speeds. Temperature, water, oxygen, and light are all known to degrade compounds, and yet many storage systems or compound access processes expose compounds to less than ideal storage conditions. Recently, some small compound storage systems have been introduced to the market that preserve compounds cold and under dry nitrogen, but large systems typically don’t have this option because of the requirement for technicians to enter the system. Another key feature to a compound storage system is the ability to quickly access large sets of individual compounds. Historically, this bottleneck has been inherent to compound management and has limited the usefulness of compound libraries. Discovery Partners has recently introduced medium to large systems that can store compounds at –20 °C under dry nitrogen and can “cherry pick” compounds at a rate of tens of thousands per day. This presentation will discuss the opportunities this creates for more efficient primary screening, hit follow up, library maintenance, and decentralization of compound management – all of which ultimately improve HTS performance. Discovery Partners has also been charged with maintaining the NIH compound repository, and the NIH process will be described.

- 58 -


Thursday 21st July 2005

Synthesis and screening of Combinatorial Libraries

Diversity-oriented synthesis of linear and cyclic peptidomimetic libraries with biological activity

Pierfausto Seneci1, Leonardo Manzoni1 and Carlo Scolastico1

1Department of Organic and Industrial Chemistry, University of Milan and Centre for Biomolecular Interdisciplinary Studies and Industrial Applications (CISI), Milan

[email protected]

At CISI we are exploiting several structural scaffolds to produce meaningful chemical diversity for pharmaceutical purposes, which will then be used both for chemical genetics (target identification and validation studies in plants and animals) and for the discovery of novel hits in various therapeutic areas. A project based on 5,5-, 6,5- and 7,5-fused aminoacidic scaffolds with 1-aza-2-oxobicyclo[X.3.0]alkane structures 1, representing an Ala-Pro dipeptide mimetic motif will be introduced. The strategy to use them as core scaffolds for linear or cyclic peptidomimetic libraries L1 and L2 will be described; the synthesis of a small, biologically active solution library will be presented, together with the planned SP route towards large, diversity oriented libraries. The assessment of different linker strategies; the construction on SP of scaffolds 1 through different synthetic routes; the decoration of some functional groups present on the scaffolds; and the assembly of linear and cyclic target libraries L1 and L2 will be discussed.

(n) NCOOH

ONH2

R

*

*

1

(n) NCOOH

OHN

R

*

*

X1X2 X3

(n)Xn

(n) N

OHN

R

*

*

X1X2

X3

(n)Xn

O

L1 L2

X1,2-n: building blocksR = scaffold decoration

n= 0, 1, 2*: stereochemically

defined centres

- 59 -


Combinatorial approaches for screening superagonists and antagonists in T-cell-mediated and in innate immune responses

Günther Jung1, Tobias Seyberth1, Burkhard Fleckenstein2, Renate Spohn3, Karl-Heinz Wiesmüller4

1Institute of Organic Chemistry, University of Tübingen, 72076 Tübingen, Germany; 2Rikshospitalet, University of Oslo, 0027 Oslo, Norway; 3EMC microcollections GmbH, 72070 Tübingen, Germany

[email protected]

Peptide libraries are valuable tools in elucidating the molecular interactions in T cell mediated immune responses in a quantitative way. Databases describing perfectly the allele-specific peptide binding were generated using MHC molecules associated with various autoimmune diseases: juvenile chronic arthritis, myasthenia gravis, coeliac disease or multiple sclerosis. The databases are used to develop directed peptide libraries and to study antigen recognition of T cells from autoimmune disease-patients. New strategies to modulate HLA restricted T-cell response are investigated using antagonists, e.g. peptidomimetics. In innate immune responses cell activation by lipoproteins is induced through their interaction with Toll-like receptors (TLR). Immunisations with lipopeptide-epitope constructs led to a long-lasting protection against virus challenge and efficient priming of virus-specific cytotoxic T cells. Combinatorial S-[2,3-bis(acyloxy)-cysteinyl] peptide collections were investigated in cellular assays. Deconvolution led to defined lipopeptides with improved adjuvanticity. TLR mediated cellular response also depends on the chirality and oxidation state of the S-[2,3-dihydroxypropyl]-cysteine core structure. The first known antagonists of TLRs based on lipolanthionine peptide libraries were synthesized as potential lead structures for the treatment of symptoms of inflammation and septic shock.

- 60 -


Synthesis of Library of Peptidoglycan Fragments for Elucidation of Their Action Mechanism in Immunostimulation

Yukari Fujimoto1, Seiichi Inamura1, Akiko Kawasaki1, Osamu Kubo1, Zen-yu Shiokawa1, Atsushi

Shimoyama1, Hiroomi Tokimoto1, Shoichi Kusumoto1, Gabriel Nuñez2, Naohiro Inohara2, Koichi Fukase1

1Department of Chemistry, Graduate School of Science, Osaka University, Japan; 2Department of Pathology, University of Michigan Medical School, U.S.A.

[email protected]

We previously demonstrated that the minimum structure required for the immunostimulation by bacterial peptidoglycan is N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide: MDP) but the activity of MDP recently proved to be not identical with that of peptidoglycan. In order to investigate the action mechanism of peptidoglycan, we synthesized various peptidoglycan fragments, i.e., mono-, tetra- and octasaccharides having di-, tri-, tetra- or pentapeptides. We found that these fragments showed the activity via an intracellular receptor Nod2, which is implicated in susceptibility to Crohn's disease. We also found that Nod1 recognized a dipeptide �-D-glutamyl-meso-diaminopimelic acid (iE-DAP), which is a partial structure typical of Gram-negative bacterial peptidoglycan. We now apply a library method for searching the potent ligands, and new approaches for solid-phase synthesis of peptidoglycan partial structures will be also reported.

- 61 -


Supported Reagents

A new, efficient coupling reagent for High-Throughput-Synthesis: Polymer-supported IIDQ

Eric Valeur1 and Mark Bradley1

1Combinatorial Centre of Excellence, School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ [email protected]

Polystyrene-IIDQ is a polymer-supported coupling reagent synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent couples carboxylic acids to amines in good yields and high purity without the requirement of a pre-activation step. Importantly the order of addition of the amine, acid or coupling agent makes no difference to the efficiency of the coupling reaction. PS-IIDQ is more efficient than commercially available polymer-supported carbodiimides PS-EDC and PS-DCC, and gives higher yields than HATU for general amide bond formation, including anilines and hindered substrates, such as aminoisobutyric acid or phenylglycine, even when employing an activation time for HATU. PS-IIDQ was also evaluated on a library of five carboxylic acids and ten amines, including secondary amines, giving an average isolated yield of 73%. Further characteristics of the reagent include stability under normal laboratory storage conditions and the possibility for easy recycling.

Cl

RCO2H

O

N O

O O

PS-IIDQ

3 steps

R'NH2 RCONHR'(50 examples, 73% average yield)

(recycling)

- 62 -


The scope of polymer-supported Mukaiyama reagent for the preparation of solution-phase libraries

Stefano Crosignani,1 Dominique Swinnen1

1Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Switzerland [email protected]

A polymer-supported version of the popular Mukaiyama reagent (2-chloropyridinium iodide) was prepared in one easy step from commercially available Wang resin. This reagent could be used to promote the coupling of carboxylic acids and amines or alcohols to give the corresponding amides or esters with high yields and high purities without need for any purification of the product. The complete chemoselectivity of the coupling of carboxylic acids with β-aminoalcohols to give exclusively N-acylation was exploited in order to develop a practical one-pot protocol for the preparation of libraries of 2-oxazolines. Polymer-supported tosyl chloride was used for the cyclisation step in order to obtain 5-unsubstituted oxazolines. However, when polymer-supported 2-fluoropyridinium triflate was used for the cyclisation, 5-substituted 2-oxazolines could be obtained, something which was not possible using the currently available polymer-supported reagents. A similar acylation-cyclisation procedure was developed for the preparation of 1,2,4-oxadiazoles.

- 63 -


ESCS Publication Award Lecture: Tandem Lecture

HT-materials science, QCAR and materials modeling

Wilhelm F. Maier1 and Jens Scheidtmann1

Technische Chemie,Universität des Saarlandes, Am Markt, Zeile 3, Saarbrücken, Germany [email protected]

The equipment and strategy to do combinatorial materials and catalysis research will be presented. The problems associated with discovery and development of materials is addressed. Prerequisites for correlation of materials properties with structure or composition are discussed. Examples for successive correlations of materials properties with chemicals composition are presented. This includes searching of complex parameter spaces and modeling of experimental data, prediction of optima. Special emphasis will be paid to “kriging”, searching and knowledge discovery.

- 64 -


Peptide Based Catalysis

Peptide-Based Diversity for Catalytic Asymmetric Reactions

Scott J. Miller1

1Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, MA, U.S.A.

[email protected]

Modern organic synthesis depends heavily on the use of catalysts for selective transformations. We have discovered a class of synthetic peptides that catalyze a number of enantioselective reactions. This lecture will describe the discovery and use of oligomers containing histidine and thiazolylalanine for a number of asymmetric bond formations. The connections between peptide sequence and stereoselectivity will be explored in a range of mechanistically distinct reactions. Prospects for generalizations and eventual design of catalysts from first principles will be evaluated.

R6HNNHR5

SC N

Et

O

R2HNNHR1

N N

O

R5HNNHR3

N N

O

MeBn

- 65 -


Towards Solid Supported Combinatorial Libraries of Highly Selective Peptide Based Phosphine and Oxazoline Transition Metal Catalysts

Christian A. Christensen1 and Morten Meldal1

1SPOCC Centre, Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark [email protected]

High-throughput screening of combinatorial libraries of highly selective catalysts would be an invaluable tool in organic synthesis. Thus a convenient and efficient synthesis of combinatorial catalyst libraries is in demand. The work presents new methodologies for the solid-phase synthesis of peptide based phosphine and oxazoline ligands, thereby combining the catalytic properties of classic P-P and P-N transition metal complexes with the selectivity imposed by a folded peptide. Peptide scaffolds possessing secondary amines were synthesised using commercially available Fmoc-protected amino acids and readily available Fmoc-protected amino aldehydes, in standard solid-phase peptide synthesis. This synthesis is ideal for the generation of libraries using split/mix combinatorial techniques. In situ generation of oxazoline moieties and phosphinylation of the secondary amines followed by complexation with palladium (II), readily afforded catalytically active solid supported complexes. The resin bound catalysts were successfully applied in the palladium catalysed asymmetric allylic substitution reaction. High-throughput screening methods are currently being developed.

- 66 -


Peptides as Asymmetric Catalysts for Aldol Reactions

Philipp Krattiger1, Jefferson D. Revell1, Roman Kovasy1 and Helma Wennemers1

1Department of Chemistry, University of Basel, St. Johanns Ring 19, CH-4056 Basel, Switzerland [email protected]

Peptides and amino acids are ubiquitous as chiral auxiliaries and ligands of metal-based catalysts. Far less explored is the use of peptides as metal-free catalysts. We have addressed the question whether peptides can function as efficient catalysts of aldol reactions. The many degrees of freedom of even simple peptides and the still limited understanding of the driving forces of selective catalysis renders the rational design of catalytically active peptides difficult. We therefore tested many tripeptides simultaneously for their catalytic activity by a combinatorial approach, using the method of “catalyst-substrate co-immobilisation”. Therefore an encoded split-and-mix library of tripeptides was prepared at one end of a bifunctional linker and an acetone derivative was attached to the other end. When this library was mixed with a dye-marked benzaldehyde derivative only a few beads picked up the color of the acetone derivative and remained colored even after extensive washings.

HN

NH

O

NH

HN

O

AA1-AA2-AA3-Hspacer

spacer

O

O

O

H

DMF

dye

Screening for aldol catalysts by catalyst-substrate co-immobilisation

- 67 -


Poster Presentations

Using Combinatorial Libraries to Search for Bio-active Pyrene-Derivatized Cyclic D, L-α-Peptides

Mohammad Al-Sayah1, James Fletcher2, M Reza Ghadiri3

1Department of Biology and Chemistry, American University of Sharjah, UAE; 2Department of Chemistry, Creighton University, NB, U.S.A.; 3Department of Chemistry, The Scripps Research Institute, La Jolla,

CA, U.S.A. [email protected]

Cyclic D, L-α-peptides can be designed to spontaneously partition into lipid and cell membranes and self-assemble into functional pores that facilitate ion and small molecule transport across the membrane leading to cell death. Bioactive cyclic D, L-α-peptides derivatized with pyrene fluorophores were designed to study and correlate the rates of the assembly process with the cell death rates utilizing the fluorescence characteristics of pyrene as the analytical tool. A combination of rational and combinatorial procedures was used to search for the most active and best suitable pyrene-labeled cyclic peptide for the study. This combination allowed narrowing the scope of the library toward the most effective arrangement of amino acids and the attachment position of the pyrene ring on the cyclic peptide. As a result, a couple of pyrenelabeled cyclic D, L-a-peptides were selected to complete the fluorescent study.

- 68 -


Integrated combinatorial and technological setups for efficient MedChem support

Hartmut Beck1

1Bayer HealthCare, D-42096 Wuppertal, Germany [email protected]

In times when most pharmaceutical companies strengthen their efforts to achieve optimum efficiency in their drug finding process, combinatorial and technological setups still prove to be a key success factor. Among the “lessons learned“ is undoubtedly the awareness that gigantism and automation at large scale do not necessarily help in finding high quality lead candidates. Today the perception is widespread that a well balanced technology mix serves the task to flexibly support MedChem projects at various stages. This talk will focus on key elements of our highly optimised combinatorial workflow at Bayer HealthCare in Wuppertal. We employ both solution and solid phase synthesis platforms delivering diverse compound sets for MedChem projects. Depending on library design aspects different techniques as Irori, FlexChem, Bohdan etc. are being employed. Solid phase combinatorial chemistry using split and mix techniques (Irori) usually comes into play when points of library diversity fall into early synthesis steps and when more than two points of diversity are needed. Solution phase chemistry is of great value when building block-based proposals with high degree of parallelisation at the final synthetic step are required. Using high throughput preparative LC-MS purification all compounds are purified to reach a common quality standard. Overall objective is to ensure that we deliver fast response-libraries to impact exploratory and strategic drug finding projects. Examples of successful applications will be given.

- 69 -


High Throughput Synthesis and Electrochemical Screening of Non-Pt Binary Thin Films for Oxygen Reduction

Karen Brace,1 Samuel Guerin1 and Brian Hayden2

1Ilika Technologies Ltd., CEI, University of Southampton, Southampton, SO17 1BJ; 2School of Chemistry, University of Southampton, Southampton, SO17 1BJ

[email protected]

High throughput methodologies have been applied to the synthesis of continuous thin film binary alloys supported on micro-fabricated electrochemical arrays. These materials have been screened for activity towards the reactions relevant to, and occurring in, polymer electrolyte fuel cells. In particular, the activity of non-platinum based binary alloys has been evaluated for the oxygen reduction reaction. The thin film catalyst samples were prepared using controlled and simultaneous physical vapour deposition methods in a modified MBE system. The deposited materials were characterised using EDS. Electrochemical characterisation and assessment of activity was carried out using equipment and software specifically developed for high throughput screening.

- 70 -


An Electrochromic Counter Electrode for the Combinatorial Discovery of Electrochemical Materials

Karen Brace2, Brian Hayden1 and John Owen1

1School of Chemistry, University of Southampton, Southampton, SO17 1BJ; 2Ilika Technologies Ltd., CEI, University of Southampton, Southampton, SO17 1BJ

[email protected]

High throughput electrochemical screening is a powerful tool in the discovery of new fuel cell electrocatalysts. However the need for multi-channel current followers and/or potentiostats, as well as electronically isolated electrode arrays adds to the complexity and expense of the methodology and limits the number of samples that can be tested simultaneously. An optical method of detecting electrochemical activity is an ideal first screen as it would be fast, truly parallel and involve low cost instrumentation. We have developed an electrochromic counter electrode that also acts as a direct optical screen. In this work the electrochromic counter electrode (WO3 coated conducting glass) is used to measure methanol oxidation of Pt black and PtRu/C fuel cell electrocatalytic inks deposited onto 8x8 and 2x2 arrays of glassy carbon electrodes. The spatial and time resolved absorbance changes of the electrochromic film are then recorded with a camera. For the purpose of testing the accuracy and sensitivity of these absorbance changes, the current response at each of the working electrodes were also recorded using a 64-channel current follower. Subsequently the charge passed at each of the working electrodes is directly proportional to the absorbance change of the electrochromic counter electrode at a point directly opposite.

- 71 -


Thiohydantoins – a technique for labelling peptides and proteins

Carole Brückler1, Mark Bradley1

1Joseph Black Building, School of Chemistry, University of Edinburgh, Edinburgh, EH9 3JJ [email protected]

Proteomics relies on 2D, comparative, electrophoresis of labelled proteomes allowing protein profiles to be determined in response to cellular stimulation. A key requirement is to efficiently label the cell proteome population with specific fluorophores in such a way that their mobilities and properties are not altered. The objective of this work was to develop a method to control site specific labelling of proteins and peptides that would enhance current techniques in this field (e.g. 2D difference gel electrophoresis). The project was based on carboxy terminal sequencing, which provides an elegant method of converting a C-terminal amino acid into a good leaving group and thus a handle for attaching a fluorophore. Thiohydantoins were displaced successfully with amines, hydrazines, hydrazides and thiols. This also gave access to a new route to synthesise peptidyl thioesters and thus native chemical ligation.

Scheme: Mechanism of tagging

DerivatisationPeptide N O

O R

NHS

Peptide NH

O R

O

TaggingPeptide N

H

OTAG

HN

R

NHS

H2N-TAG

Thiohydantoin

OOH

- 72 -


Fluorescein-based amino acids for solid phase synthesis of fluorogenic substrates: A new tool for high throughput screening of protease inhibitors.

Olga N. Burchak,1 Laurent Mugherli,1 François Chatelain,1 Maxim Y. Balakirev1

1Laboratoire Biopuces, Département Réponse et Dynamique Cellulaires, Commissariat à l’Energie Atomique, 17 rue des Martyrs, 38054 Grenoble, France

[email protected]

Fluorogenic substrates allow for the continuous kinetic analysis of protease and are useful reagents for screening potential protease inhibitors and for determining protease substrate specificity. We have found an efficient synthesis of new type fluorescent amino acids. The Fmoc-protected dyes can be prepared in 4-steps procedure with 40% overall yield from aminofluoresceins and other commercially available precursors. These fluorescent compounds are much more photostable compared to fluorescein and exhibit constant pH-independent fluorescence that is advantageous in biological applications. As a proof of concept, we synthesized a fluorogenic papain substrate based on one these fluorophores using Methyl Red as a fluorescence quencher, and demonstrated its application for direct measuring papain activity on TentaGel beads. By using a novel technique for quantitative analysis of bead fluorescence, ~2.7 fold increase in mean bead brightness was measured and was attributed to substrate cleavage by papain. The synthesized amino acids seem to be promising tool for obtaining of fluorescent peptide ligands and fluorogenic protease substrates.

- 73 -


Microwave-assisted Esterification reactions using isoureas

Alessandra Chighine1, Stefano Crosignani2, Bruno Linclau2 and Mark Bradley1

1School of Chemistry, University of Edinburgh, King’s Buildings, Edinburgh, EH9 3JJ; 2School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ

[email protected]

The use of microwave irradiation is a topic of increasing interest in synthetic chemistry because reactions by virtue of increased temperatures are speeded up and there is often an increase in the purity and in the yields of the products compared to conventional heating methods. We developed a microwave-assisted synthesis of esters utilizing solid supported O-alkylisoureas. Using this solid supported reagent, it was possible obtain esters in high purity and yields with short reaction times. We also studied the same reaction using soluble isoureas generated in situ and a nearly equimolar amount of acids and alcohols. In this way we used microwave irradiation for rapid chemistry and stoichiometric amounts of alcohols and acids for atom efficiency.

- 74 -


Palladium Captured and Fixed within Polystyrene-Poly(ethylene glycol) Resins

Jin Ku Cho1, Tony W. Dean2, Osamu Ichihara3, Christophe Muller3, and Mark Bradley2

1Combinatorial Centre of Excellence, School of Chemistry, The University of Edinburgh, Edinburgh EH9 3JJ, UK, 2GlaxoSmithKline, Discovery Research, Gunnels Wood Road, Stevenage SG1 2NY, UK, 3Evotec

OAI, Milton Park, Abingdon, Oxon OX14 4SD, UK [email protected]

Palladium is among the most popular transition metals in modern organic synthesis and widely used for a significant number of organometallic reactions. A number of groups have immobilized a variety of palladium catalysts onto a number of insoluble supports, enabling easily separation of palladium from the desired product and reuse, ideally without loss of catalytic activity, thereby providing a practical and economic advantage especially with respect to large scale operation and multiple parallel synthesis. Here, we wish to report that palladium “nanoparticles” or even isolated “molecular Pd (0)” can be captured by a resin backbone without the assistance of any resin-bound ligand and permanently fixed via crosslinking of the terminal amino groups on the resin. The concept was that soluble Pd (OAc)2 would diffuse into swollen resin, following which the amino groups on the resin would be “tied and tangled” by cross-linking. The resulting supported Pd was found to be reliable for heterogeneous Suzuki coupling reactions in water, could be handled in air with precautions and re-used without significant loss of activity.

- 75 -


Integration of New Technologies in High Throughput Chemistry

Elizabeth Conway1, David Corbett, John Darker, Dave Hunter, Tom Smith, Jason Tierney, Rob Webster 1GlaxoSmithKline, New Frontiers Science Park, Harlow, CM19 5AW

[email protected]

In recent years, the pharmaceutical industry has come under increasing pressure to reduce cycle times and rates of attrition in drug development whilst maintaining high standards of safety and quality of the new medicines it produces. The response from industry has been evident in genomics and high throughput screening, where, along with high throughput chemistry, technology has dramatically changed the dynamics of the drug discovery process. The Discovery Research Automation Facilities (DRAF) at GSK enables an integrated approach to high throughput chemistry. Drop-down services in these open plan laboratories create flexible work areas, enabling the efficient production of a large number of single compounds. A number of array synthesis platforms are utilised, in particular the IRORI X-KanTM and ClevapTM technology. The integration of a large scale microwave synthesiser (Biotage AdvancerTM) will also be described.

- 76 -


LC-MS coupled with chemiluminescent nitrogen detector for on-line quantitative analysis of compound collections: advantages and limitations

David Corens1, Michel Carpentier, Marc Schroven, Lieven Meerpoel

1Synthesis Enabling Technology Group, Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V., Turnhoutseweg 30,

B-2340 Beerse, Belgium [email protected]

Recently, alternative detection methods such as chemiluminescent nitrogen detection (CLND) have been coupled successfully with HPLC for quantification. This detector produces a signal proportional to the number of moles nitrogen present in the compound. Sample concentration of compounds with a known formula can be determined by use of an external calibration standard such as caffeine. Hence, the CLND can be used without the need for primary standards of the compound with unknown concentration, which enables the use of this detector for high-throughput analysis. In this presentation, the reliability and pitfalls of this coupled LC-MS/CLND are demonstrated. Nitrogen detection is specific as it only gives a response for nitrogen containing compounds and universal since it only gives a linear response. Nevertheless the lower response for N=N and N-N containing compounds has also been evaluated.

- 77 -


A Parallel, High Throughput Approach to Liquid Crystal Screening

Tobias Cull1, Mark Bradley1

1School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ [email protected]

The increasing use of High Throughput (HT) methods in the formulation of liquid crystal materials has necessitated the development of devices for HT screening of LC properties to keep pace with formulation. A new device enabling screening of LC phase transitions using optical anisotropic effects, observed only in the LC state, allows the determination of melting and clearing points of a range of LCs. When compared with literature and conventional differential scanning calorimetry, the new technique was found to be in excellent agreement, establishing the technique as a viable alternative. Techniques for the formulation of large libraries using robotic liquid handling were developed, and the device was used to analyse such libraries to identify transitions over 3-dimensional phase space. By the continued development of new HT techniques and by the use of robotic liquid handling, new LC formulations can be quickly and easily analysed, enabling optimal properties to be obtained.

- 78 -


A library synthesis of cyclic depsipeptides, beauveriolide and its analogues, using polymer-support

Takayuki Doi1, Kenichiro Nagai2, Takafumi Sekiguchi1, Yusuke Iijima1, Takashi Takahashi1,

Ichiji Namatame2, Toshiaki Sunazuka2, Hiroshi Tomoda2, and Satoshi Omura2

1Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo 152-8552, Japan, 2Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University and The

Kitasato Institute, Tokyo 108-8641 Japan [email protected]

Beauveriolides III, isolated from the culture broth of Beauveria sp. FO-6979, leads to a reduction in the number and size of lipid droplets in macrophages without any cytotoxic effect and also inhibits cholesteryl ester (CE) synthesis, leading to suppression of foam cell formation in macrophages. In order to elucidate the structure activity relationships and to discover a new drug lead, we have studied a method for rapid synthesis of beauveriolide and its analogues. Solid-phase peptide synthesis by Fmoc strategy provided a variety of linear precursors in a combinatorial manner and cyclization was achieved in solution phase. Finally, preparative reversed-phase HPLC provided beauveriolide analogues in pure form. Effect of each substituent on the macrocycle for inhibitory activity of the CE synthesis will be discussed.

Cl

NH

NH

O

HN

O

OO

O

beauveriolide III

CO2HO

BocHN

O

R1

HO2C

FmocHN

NHFmocHO2C

Y

X

++

+

cyclization

R2

_

- 79 -


A Mild Protocol for Parallel Solution Phase Synthesis of Cyclic Imides

Andrew R. Extance,1 David W.M. Benzies1 and Daniel Hurlbut1

1Tripos Discovery Research, Tripos Discovery Research Centre, Bude-Stratton Business Park, Bude, Cornwall, EX23 8LY

[email protected]

Cyclic imides (1) are a class of compounds with pharmacologically attractive attributes, the functionality being present in both biologically active investigational compounds and marketed drugs. Production and screening of libraries of such compounds is therefore of interest in the search for new medicines. Conventional syntheses of cyclic imides from amines and cyclic anhydrides use relatively forcing conditions that are not appropriate for performing large numbers of simultaneous discrete reactions. A solution phase synthesis of cyclic imides using carbonyl di-imidazole (CDI) in DCE at a moderately elevated temperature is described as a mild and effective alternative to these methods.

- 80 -


Microwave-assisted Radical Reactions for Solid-phase Synthesis

Koichi Fukase, Hisashi Akamatsu, Hiroomi Tokimoto, Shoichi KusumotoDepartment of Chemistry, Graduate School of Science, Osaka University, Japan

[email protected]

Microwave-assisted radical reactions for solid-phase synthesis of indol-2-ones and oligosaccharides are described. Indol-2-ones were efficiently synthesized by means of aryl radical cyclization of resin bound N-(2-bromophenyl)acrylamides using Bu3SnH. Among various solvents tested, DMF was found to be the best choice for the radical cyclization inducing a reagent concentration effect of the polymer support. The reaction proceeded smoothly under microwave irradiation to give the desired indol-2-ones within very short reaction time. 2,2,2-Trichloroethoxycarbonyl (Troc) group has been frequently used for protection of amino and hydroxy groups but can not apply to solid-phase synthesis, since heterogeneous conditions, e.g., Zn-AcOH, are required for the removal of Troc group. In this study, we developed a new method for deprotection of N-Troc group by using (Bu3Sn)2 in DMF under heating. The reaction was dramatically accelerated by microwave irradiation. Troc group of resin bound N-Troc glucosamine was efficiently removed by this method. Application of this method to solid-phase synthesis of oligosaccharides is also reported.

- 81 -


A traceless PerfluoroarylSulfonyl Linker for Palladium (0) Mediated Microwave Reactions

Luciano Galveia1 and Mark Bradley1

1Combinatorial Centre of Excellence, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ

[email protected]

A tetrafluoroarylsulfonyl chloride linker was developed, and reacted with a small number of alcohols substrates to give supported arylsulfonates. Most linkers leave a residue attached to the cleaved molecule; that is the functional group (or a derivative thereof) used to attach the molecule to the linker, i.e., a carboxylic acid, an amide, or an alcohol. Since this is not always desirable, the investigation of a perfluorosulfonyl chloride linker that leaves no obvious residue on the cleaved molecule, traceless linker, was carried out. Several protocols were investigated regarding palladium (0)-mediated diversification under microwave irradiation, allowing transfer hydrogenation, Suzuki-Miyaura and Stille cross-coupling as well as carbon-nitrogen cross-coupling based on Buchwald’s chemistry. The optimized conditions were then tested with a small number of alcohols providing cross-coupling in good to excellent yields in most cases, showing the versatility of the linker as well as its reliability when used under microwave irradiation.

- 82 -


Preparation and screening of combinatorial insulin mixtures for identification of self-assembled, long-acting components

Thomas Hoeg-Jensen1

1Novo Nordisk, Novo Alle 6B2.54, DK-2880 Bagsvaerd, Denmark [email protected]

Prolongation of the in vivo half-life of peptide and protein drugs is often desired. This objective has been pursued among other by derivatizing peptide or protein drugs with motifs that increase the self-assembly of the drugs in for example subcutaneous depots. As illustration, T½ of monomeric insulin is 1 h, T½ of hexameric insulin is 2 h, whereas T½ values of insulins that form large soluble self-assemblies can be >10-20 h. Combinatorial synthesis and screening of insulins mixtures for self-assembled components is reported here. The screening method utilizes size-exclusion chromatography for collection of high-molecular weight components with subsequent identification by mass spectrometry. The methodology should be generally applicable in screening for soluble self-assembled and hence long-acting peptide and protein drugs.

- 83 -


Solid-phase Synthesis of Substituted 1,N6-Ethenoadenines

T. Karskela, H. Lönnberg

Department of Chemistry, University of Turku, Turku, Finland [email protected]

Protein kinases constitute an important group of targets for drug discovery. Several potential adenine based kinase inhibitors have been prepared by parallel solid-phase synthesis. 2´-Deoxyadenosine 3´-monophosphate attached to a solid support via a phosphodiester linkage was converted to 1,N6-formyletheno-2´-deoxyadenosine with bromomalonaldehyde. The first randomizable substituent was inserted by reductive amination and the second attached to the secondary amine obtained. After possible further reactions at the substituents the completed molecules were cleaved from the solid support by depurination.

N

NN

NH

N N R1

R2

R1 = alkyl substituentR2 = alkyl or acyl substituent

- 84 -


Solid-phase synthesis of oligonucleotide glycoconjugates bearing three different glycosyl groups: orthogonally protected bis(hydroxymethyl)-N,N’-

bis(hydroxypropyl)-malondiamide phosphoramidite as key building blocks

J. Katajisto,1 P. Heinonen,1 and H. Lönnberg1


Covalent conjugation of carbohydrates to oligonucleotides has gained increasing interest during recent years as it offers a convenient way to enhance binding of antisense oligonucleotides to a certain cell type and thus improve their cellular intake by endocytosis. We herein report on a facile method of preparation of diverse oligonucleotide glycoconjugates. A phosphoramidite derived from bis(hydroxymethyl)-N,N´-bis(3-hydroxypropyl)malondiamide that contains three orthogonally protected hydroxyl groups (1) and is compatible with normal chain assembly has been used as a key building block. Stepwise removal of the 4,4´-dimethoxytrityl (DMTr), levulinyl (Lev) and tert-butyldiphenylsilyl (TBDPS) protections followed by coupling of a glycosyl-derived phosphoramidite to the exposed hydroxyl group gives the desired oligonucleotide glycoconjugate. The applicability of this approach has been demonstrated by preparing both T6 and a heterosequence bearing three different sugar units, viz. mannose, galactose and glucose.

DMTrO NH

O N

O

O

OTBDPS

OLevHPMeO

N

1

OP

O-O O

OO

HN

HN

O

OPOO

-O3' TATCTAGCAGT

O-T

OOH

HO

OMeOH

OP-O

O

OHO

HO

OMe

OP-O OH

O

OHO

HO

OMe

OPO

-O

OH

O

- 85 -


Pentaerythrityltetramine scaffolds for solid-phase combinatorial chemistry

M. Leppänen,1 P. Virta1 and H. Lönnberg1


Solid-supported scaffolds bearing orthogonally protected functional groups on a compact branching unit have received interest in the generation of combinatorial libraries. We have recently reported a synthesis for two pentaerythrityltetramine precursors (1 and 2). Both scaffolds have been attached by reductive amination to a solid-supported backbone amide linker (3). The remaining free primary amino group of the scaffold moiety (4) may be selectively acylated using conventional DCC/HOBt activation. The secondary amino function may be subsequently acylated by an anhydride method. Sequential reduction of the azido group and removal of the allyloxycarbonyl protection from 2 allow construction of branched structures containing four different amino acids or peptides. Solid-supported 1 may, in turn, be used for the synthesis of similar constructs containing two identical branches (R3 = R4). The applicability of the scaffolds to library synthesis has been demonstrated by preparation of pentaerythrityl-branched peptides (5).

NH

HNHN

NH

O

O

AcHN

AcHN

ONHAc

O

NHAc

R1

R2

R4

R3

X

N3NH3

+ TFA-

NH3+ TFA-

1: X = N3 2: X = NHAlloc

SPPS

5

X

N3NH2

NHOMe

MeO

O

3, NaCNBH3

4

- 86 -


Solid-Phase Synthesis of Bicyclic Dipeptide Mimetics by Intramolecular Cyclization of Alcohols, Thiols, Amines and Amides with N-Acyliminium Intermediates

S. Le Quement,1 T.E. Nielsen,1 M. Meldal1

1Carlsberg Laboratory, SPOCC-Centre, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark [email protected]

Peptides and peptido-mimetics displaying bicyclic conformational constraints have been widely investigated probes for the mimicry of secondary structural elements, which are often critically important for the molecular recognition of bioactive peptides with receptors, enzymes and antibodies. Taking advantage of intramolecular condensation reactions of peptide aldehydes with the amide backbone, generating synthetically versatile cyclic N-acyliminium ions, we now wish to report a highly efficient and general strategy for the solid-phase assembly of a range of renowned, yet structurally diverse, bicyclic dipeptide mimetics. A general strategy for the solid-phase synthesis of structurally diverse bicyclic dipeptide mimetics is presented. Depending on the amino acid side-chain (R), peptide-derived N-acyliminium intermediates may undergo nucleophilic attack from either side-chain functional groups (-OH, -NH2, -SH, and -CONH2) or the amide backbone (-CONH-) of the peptide, thus affording a range of aza-, thia-, and oxabicycloalkanes in excellent purity and diastereo-selectivity (both up to >95%).

- 87 -


High Throughput Synthesis and Electrochemical Screening of Ternary Thin Films for Oxygen Reduction

Samuel Guerin,1 Brian E. Hayden,1 Christopher E. Lee,1 and Claire Mormiche1

1Department of Chemistry, University of Southampton, UK, SO17 1BJ [email protected]

High Throughput methodologies have been applied to the synthesis of continuous thin film binary and ternary alloys supported on micro-fabricated electrochemical arrays. These materials have been screened for activity towards the reactions relevant to, and occurring in, polymer electrolyte fuel cells. In particular, the activity of platinum based binary and ternary alloys has been evaluated for the oxygen reduction reaction. The thin film catalyst samples were prepared using controlled and simultaneous physical metal deposition methods in a modified MBE system. The deposited materials were characterized using EDX and AFM. Electrochemical characterisation and assessment of activity was carried out using equipment and software specifically developed for high throughput screening. To date, these experiments have identified several material compositions that exhibit promising electrochemical activity relative to Pt for the reduction of oxygen.

- 88 -


High Throughput Synthesis and Electrochemical Screening of Palladium-Copper Thin Films for the Reduction of Nitrate

Martin Bennett,1 Samuel Guerin,1 Brian E. Hayden,1 and Christopher E. Lee2

1Department of Chemistry, University of Southampton, UK, SO17 1BJ; 2Ilika Technologies Ltd, Centre for Enterprise and Innovation, University of Southampton, UK, SO17 1BJ

[email protected]

High Throughput methodologies have been applied to the synthesis of continuous thin film binary Pd-Cu alloys supported on micro-fabricated electrochemical arrays. These materials have been screened for activity towards the electrocatalytic reduction of nitrate in an alkaline electrolyte. The thin film catalyst samples were prepared using controlled and simultaneous physical metal deposition methods in a modified MBE system. The deposited materials were characterized using EDX and AFM. Electrochemical characterisation and assessment of activity was carried out using equipment and software specifically developed for high throughput screening. These screening experiments have identified material compositions that exhibit electrochemical activity that is superior to that of the individual alloy components.

- 89 -


High throughput screening of inkjet materials

José María López Pedrosa1 and Mark Bradley1

1 School of Chemistry, University of Edinburgh, King’s Buildings, Edinburgh, EH9 3JJ [email protected]

Improvements in the formulation of aqueous based dyes for inkjet applications were determined by the preparation of up to ninety-six formulations using liquid handling robotics. The formulations were prepared using standard solutions of the various components of the inkjet materials although special care was necessary in order to enable good aspiration and dispensing of the viscous components (in particular PEG-10000MW, with a 4mPaxs viscosity). Dispensing was carried out randomly using the statistic techniques (ANOVA). Important physical properties such as dynamic viscosity and colour fading were determined in a HT manner in order to optimize the best formulation.

- 90 -


A Device to Rapidly Address Ternary Phase Diagrams and Explore Multi-component Space

Yucheng Luan1 and Mark Bradley1

1School of Chemistry, King’s Buildings, University of Edinburgh, Edinburgh EH9 3JJ [email protected]

A novel device was demonstrated, enabling the combinatorial approach to the ternary phase diagrams with both liquids and low melting point solids. With this device ternary mixtures were easily made without the need to calculate and weigh the component. Pluronic P105(EO POEO)-TEOS-HCl (0.5M) ternary system was chosen as an example and various silica nanomaterials were synthesized.

- 91 -


Fragment Based Screening: Lead Discovery for the Macrophage Migration Inhibitory Factor Using Synergistic Application of NMR, MS and X-ray Screening

A. L. Marzinzik1, C. Fernández,1 M.J.J. Blommers,1 F. Bitsch,1 A. Widmer,1 S. Lehmann,1 J.-M.

Rondeau,1 C. Zwingelstein,1 X. Pelle1

1Novartis Institutes for Biomedical Research, Basel, Switzerland [email protected]

Fragment-based screening (FBS) is emerging as a new and powerful approach to lead discovery. The aim of FBS is to identify small (150-250 Da), hence weakly binding (Kd ~ 100 mM -1 mM) fragments to a macromolecular target. Such low molecular weight compounds are usually missed by conventional screening methods but can serve as a basis for structure-based chemical elaboration to provide new leads. Protein NMR, X-ray crystallography and mass spectrometry have all been applied in parallel to screen an unbiased library of 400 low molecular weight compounds against MIF (Macrophage Migration Inhibitory Factor). The results show that NMR, X-ray and MS are highly complementary, providing overlapping but not identical sets of hits, and should therefore be applied in parallel whenever possible. Using a targeted, structure-based chemistry effort, selected FBS hits were optimized, leading to several derivatives with low micromolar to sub-micromolar inhibitory activity.

- 92 -


HTT Automation: The Big Picture

Nigel McCoy1

1Astech Projects Ltd, Unit 15 Berkeley Court, Manor Park, Runcorn, Cheshire, WA7 1TQ [email protected]

The fully automated HTT system is flexible, allowing the operator to create workflows and methods, while scheduling and executing work efficiently. Operators have a high level of control requiring minimum intervention. Automation operates unattended, scheduling all necessary transfers between discrete system components. Full automation is also capable of handling and storing vast amounts of data in a readily accessible format. The fully automated HTT system can handle many materials. Materials must be handled safely. Full automation is intrinsically safer by minimizing operator interaction, however, where intervention is required, operator safety must be considered. ASTECH’s HTT group produces fully automated HTT systems for many industries. Our poster will describe the techniques utilized by ASTECH in different HTT applications and considers each factor described above.

- 93 -


Separation of Enantiomers by Chiral Chromatography

Phillip Milnes1 and Mark Bradley1

1School of Chemistry, University of Edinburgh, Kings Buildings, Edinburgh, EH9 3JJ [email protected]

Determination of Chiral Stationary Phase Media for a given separation of pharmaceutical enantiomer is currently a slow procedure. This is achieved by screening of the pharmaceutical racemate on all previously successful commercial chiral HPLC columns. Little is know as to the interaction mechanism or the CSP-enantiomer structure to enantioseparation relationship. This poster shows key structural changes in both CSP and enantiomer which greatly affects the inherent enantioseparation. This research is aim at improving our knowledge of CSP-enantiomer interaction, increasing the confidence of chiral separation media choice and generation of an array of small and inexpensive chiral stationary phases for successful separation of pharmaceutical racemates.

- 94 -


New Linker Strategies in Solid-Phase Synthesis of Neuroactive Wasp Toxin Analogues

Christian A. Olsen,1 Jerzy W. Jaroszewski,1 and Henrik Franzyk1

1Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark

[email protected]

Natural spider- and wasp toxins [e.g., ArgTX-659 (1) and PhTX-433 (2)] as well as synthetic analogues thereof interact with ionotropic receptors including nicotinic acetylcholine receptors (nAChR) and ionotropic glutamate receptors (iGluR) in the central nervous system. These toxins block ion channels in neural cells, and they are therefore important as probes in the investigation of receptor structure and function. Recently, we have prepared hybrid analogues such as 3a-d employing a new trityl bromide anchoring strategy. The phenol group of N-Fmoc-Tyr-OPfp was immobilized under mild conditions, which enabled bidirectional synthesis of the tail-elongated PhTX-343 analogues. Furthermore, the application of a Backbone Amide Linker (BAL) protocol has been investigated for preparation of polyamine toxins.

- 95 -


Development of a high-throughput screening for Multiple Sclerosis patients’ sera based on an optical glycopeptide immunosensor

E. Peroni1, E. Bulukin2, M. Minunni2, M. Pazzagli1, P. Rovero1, M. Mascini2 and A.M. Papini1

1Laboratory of Peptide & Protein Chemistry & Biology, Polo Scientifico, Università di Firenze, I-50019 Sesto Fiorentino, Italy; 2Università degli Studi di Firenze, Dipartimento di Chimica, Polo Scientifico, Via

della Lastruccia 3, 50019 Sesto Fiorentino, Italy [email protected]

The Laboratory of Peptide & Protein Chemistry & Biology has been involved for a decade in characterizing an antibody-mediated disease pattern in Multiple Sclerosis (MS). We developed CSF114(Glc), a structure-based designed glycopeptide as the first antigenic probe able to detect sugar-specific autoantibodies as biomarkers of disease activity of a consistent population of MS patients. An optical glycopeptide-based sensor for an high-throughput screening of autoantibodies in MS patients’ serum has been developed. Optimization of the sensor was performed with anti-CSF114(Glc) antibodies purified from sera. The diagnostic/prognostic technology was validated using MS and normal blood donors’ sera as controls. The analytical parameters, such as specificity, sensitivity, matrix effect, and analysis time of the sensor were evaluated, and optimized by a comparative study with MS PepKit, our reference ELISA based on CSF114(Glc).

- 96 -


Parallel Syntheses of 2-Amino-5-alkylidene -thiazol-4-ones

Maurizio Pulici1 and Francesca Quartieri1

1Nerviano Medical Sciences, Viale Pasteur 10, Nerviano, Italy [email protected]

2-Amino-5-alkylidene-thiazol-4-one represents one of the privileged scaffolds in drug discovery, as this heterocyclic core is found in thousands of molecules endowed with biological activity. Here we disclose two alternative routes towards the parallel assembling of this type of compounds. 2-Amino-5-alkylidene-thiazol-4-ones bearing two diversity points are prepared using either a solid-phase strategy exploiting rhodanine as the starting material, or a microwave promoted multicomponent reaction in solution phase. In the former case rhodanine is first loaded on bromo-Wang resin, subjected to Knovenagel condensation with aldehydes, and cleaved off the resin in a traceless manner by means of an amine. In the latter one, the targeted compounds are obtained by heating equimolar amounts of ethyl thiocyano-acetate, aldehyde and amine.

- 97 -


Multifunctionalized Cross-Linked Microspheres as Efficient Carrier Systems

Rosario M. Sanchez-Martin1, Mathilde Muzerelle2, Stifun Mittoo2 and Mark Bradley1

1School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains road, Edinburgh EH9 3JJ; 2School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ

[email protected]

A great number of potential drugs fail due to poor bioavailability characteristics. In other words they do not possess the correct balance between lipophilicity and hydrophilicity which is crucial for the effective permeation across the lipid biomembranes that are surrounded by polar fluids. As a consequence a diverse range of carrier systems has been extensively developed to help overcome this obstacle. Varying sizes of functionalized cross-linked polystyrene microspheres were generated, fluorescently labelled and delivered into cells to function as cellular tags and probes. This allows the effective delivery of foreign materials into intact mammalian cells, without the need for delicate procedures such as micro-injection, and does not disrupt cell physiology.

- 98 -


Polymer supported peracids

Gianluca Sechi1 and Mark Bradley1

1Combinatorial Centre of Excellence, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road, Edinburgh EH9 3JJ

[email protected]

Aqueous H2O2 is an ideal clean oxidant with H2O2 concentration <60%. However the use, storage, and transportation of high concentrations of H2O2 is not safe. Although peroxide is a potent oxidant, it is often sluggish and needs to be activated. Usually it is used to oxidize a mediator, as a rule an organic or inorganic acids, which in turn oxidizes the organic substrate. Unfortunately, most of these activators (such as various metal catalyst systems) are not satisfactory for medium- to large-scale synthesis due to high costs and their environmentally unfriendly nature. The idea to find a simple procedure to utilize commercial available ion-exchange resins as activators for hydrogen peroxide to give an economic and safe alternative to the use of organic peracids, and simplifier reaction work-ups is discussed.

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A toolbox technology for 1:1 generic labeling and purification of recombinant target proteins for on-bead confocal nanoscanning and fluorescence multicolour detection

Jan-Marcus Seifert, Nicole-Claudia Meisner, Franz Amberger, Marcus Tysk, Philipp Graf, Volker Uhl,

Mario Schmied, Christine Graf, Peter Kolesik and Manfred Auer Discovery Technologies - Innovative Screening Technologies

Novartis Institutes for BioMedical Research GmbH&Co KG, Brunner Str. 59, A-1235 Vienna, Austria [email protected]

For fluorescence detection applications in quantitative biology and screening assays with a need for defined labelling stoichiometry we established a methodology for generic preparation of homogeneous, site-specifically and 1:1 labelled proteins. The target protein is coupled to a synthesized reactive peptidic reagent comprising a dye and reversible or irreversible affinity sites, separated by hydrophilic spacers and a photocleavable linker. These elements enable positioning of the label, separation from unreacted target protein and optional final removal of the affinity site. The tags are coupled either exclusively to the termini of expressed proteins with CT-thioester or NT-cysteine by native ligation between thioester and cysteine groups or by maleimide reaction to single internal cysteine. A toolbox of 30 labelling tags with different functionalities, dyes and affinity tags was prepared, and 1:1 labelled target proteins were used for on-bead library confocal nanoscanning (CONA) applications and solution fluorescence measurements as e.g. FIDA and FRET.

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Solid-phase synthesis of novel trimers of phenylstatine. Analysis by High-Resolution Magic Angle Spinning

Lorena Taboada, Lourdes Prieto, Paloma Vidal and Juan F Espinosa

Lilly S.A., Avda Industria 30, 28108 Alcobendas (Madrid), Spain [email protected]

The aim of our work was to develop a peptide trimer library containing the phenyl statine core as a central unit to explore the minimum requirements for Aspartyl Proteases inhibitors. The synthesis of peptides was achieved on solid-phase, using Fmoc chemistry for the elongation of the chain. Monitoring of reactions was performed using different techniques. In this context, High-Resolution Magic Angle Spinning (HR-MAS) NMR has been recently reported as a powerful tool for “in situ” characterization of a compound anchored to a resin. Here, we report on the use of HR-MAS for monitoring the incorporation of the amino acid residues onto the resin and for obtaining detailed structure information of intermediates and final products. HR-MAS analysis resulted in the optimization of the synthetic strategy during the library construction.

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High throughput cell screening onto polymer microarrays

Guilhem Tourniaire,1 Mark Bradley1

School of Chemistry, University of Edinburgh, Kings Buildings, Edinburgh, EH9 3AF [email protected]

The development of high throughput screening methods is essential for a better understanding of the interactions between cells and biomaterials. In this poster, we describe the development of a method using an agarose-coated substrate allowing the cellular screening of libraries of biocompatible polymers and show how such polymers can mediate cell specific enrichment and immobilisation of non-adherent cells.

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Progress towards the solid-phase synthesis of structurally diverse 1,5-benzodiazocine-2,6-diones and 1,4,5-benzotriazocine-2,6-diones for application in

combinatorial libraries

Jurgen Caroen,1 Johan Van der Eycken1 1Laboratory for Organic and Bioorganic Synthesis, Ghent University,

Krijgslaan 281 (S.4), B-9000 Gent, Belgium [email protected]

In our current work we are interested in the development of a solid-phase route towards combinatorial libraries of new pharmaceutically interesting eight-membered benzo-annulated systems represented by general formulae 1 and 2. Maximal diversity should be introducible through chemistry with a plethora of commercially available or readily accessible building blocks. An obvious and straightforward way of constructing the basic skeleton would be through an intramolecular lactamization reaction. Here we wish to present our synthetic efforts towards resin-bound open-chain model precursors and our initial reaction conditions under which the ring closure could be achieved. Several strategies featuring on-resin cyclization as well as cyclative cleavage are investigated.

N

NO

O

R1

R4

R3

R2

R5

NN

NO

O

R1

R4

R3

R2

R5

1 2

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Combinatorial approach towards the development of a new type of dipodal DNA-binding peptides

Dieter Verzele,1 Annemieke Madder1

1Ghent University, Department of Organic Chemistry, Laboratory for Organic Synthesis, Krijgslaan 281 (S4), B-9000 Gent, Belgium

[email protected]

Several proteins are involved in the transcription of DNA to mRNA, among which the dimeric basic-leucine zipper (bZIP) proteins. These dimers consist in general of a dimerization domain, rich in leucine residues, and two recognition α-helices, containing mainly basic amino acids. The aim of our research is to synthesize bZIP-like peptides on solid-phase. Because research has shown that the dimerization domain is only required to obtain the correct geometrical positioning of the α-helices relative to the DNA strand, we will replace it by the dipodal steroid scaffold 1. The general synthetic strategy is outlined in the figure below. After optimization of the reaction conditions this reaction scheme can be used in the combinatorial synthesis of libraries of dipodal peptides. An important advantage of this methodology is the use of the orthogonally N-protected dipodal scaffold 1, which allows the assembly of not only homodimers, but also heterodimers.

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A Combinatorial Approach to Solid-Phase Peptide Based N-Heterocyclic Carbene and Phosphine Ligands

K. Worm-Leonhard,1 M. Meldal1

1Carlsberg Laboratory, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark [email protected]

A series of chiral imidazolium ion building blocks, which can serve as N-heterocyclic carbene precursors, were readily synthesized. The building blocks, possessing both an amino- and carboxylic acid functionality, were cleanly incorporated in a series of solid supported peptide chains using standard solid phase peptide synthesis. Furthermore, a reduced peptide bond was introduced in the peptide backbone by means of solid-phase reductive alkylation using Fmoc-protected phenylalaninal, which was readily synthesized in solution. This procedure allows for the use of natural and synthetic pool of chiral amino acids, variation of the number of amino acids used as well as the incorporation of one or two carbenes or a mixture of one carbene and one phosphine building block into the peptide chain during the synthesis of combinatorial ligand libraries. The ligands were treated with various palladium precursors and tested in asymmetric synthesis.

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Immunoassay and Image Analysis on Microfluidic Chips

Bi-Chu Wu,1 Yu-Ching Liu,1 Su-Jan Lee,1 Chung-Kai Chen,1 Gin-Shu Young1

1Medical Engineering Technology Division, Biomedical Engineering Center, Industrial Technology Research Institute, Hsinchu, Taiwan

Microfluidic chips can be very useful to life science applications such as drug discovery or biochemistry testing. One major advantage using a microfluidic chip over the conventional tube-based tests in laboratory is that a number of fluid sample pre- and post-processing steps such as mixing, dilution, separation, or washing can be sequentially and precisely performed. In this paper an immunoassay microfluidic chip manufactured using micro system technology was constructed for the detection of a specific antigen in fluid samples. A special antibody was immobilized onto the walls of the fluid channels on the chip. In bioassay the immobilized antibody captured the labeled antigen in the fluid sample flowing through the channels. Image analysis was used to analyze the results of the antigen-antibody interaction at the reaction site. Results from the observation of antigen-antibody interaction at the reaction site of the chip were presented and discussed. The approach demonstrated the feasibility of applying a polymeric microfluidic chip to immunoassay experiments.

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Exhibitors at Eurocombi3 Activotec Ltd Contact details: Chris Littlewood Dr Michael Krusche Activotec Ltd 7 St George's Tower Hatley St George Sandy SG19 3HP Tel.: +44 (0) 1767 651166 Fax: +44 (0) 1767 651177 Email: [email protected] Web: www.activotec.com Company Profile: Activotec provides innovative custom synthesis services, instrumentation and chemicals for chemical research and development. The Company was formed in December 2002 as a spinout from the University of Southampton.

Activotec's core focus is customer service whether it's instrument support, delivery of quality custom synthesis services or chemicals, all critical to the success of your science. Activotec offers scientists a single point of expertise and assistance in research, design, manufacture of new, innovative and practical solutions. The Company develops and pioneers novel methods for the synthesis of peptides and proteins from their constituent parts, amino acids. Using these synthetic methods as an advanced technological platform, the Company is able to produce a wide range of peptides and proteins to order that are difficult to make via other techniques. The Company welcomes collaborative projects with biotechnology and pharmaceutical partners to develop new strategies for peptide and protein synthesis.

Astech Projects Ltd Contact details: Peter Greenhalgh Paul Norris 15 Berkeley Court Manor Park Runcorn, Cheshire WA7 1TQ Tel.: +44 (0) 1928 571797 Fax: +44 (0) 01928 571162 Email: [email protected] Web: www.astechprojects.com Company Profile: ASTECH Projects create bespoke automation systems for each customer’s unique

requirements. ASTECH are specialists in a number of key areas such as Inhaler and Respiratory automation, High Throughput Experimentation (H.T.E) and novel “never been done before” solutions. ASTECH also integrate existing semi-automated systems (i.e. autosamplers, powder dispensers and specialist laboratory equipment) to produce truly innovative solutions that are admired throughout the industry. ASTECH deliver automation solutions that are both robust and fit for purpose. Our key customers are in the Pharmaceutical, Life Sciences, Food and Petro-Chemical industries.

Asynt Contact details: Martyn Fordham e-space-north 181 Wisbech Rd Littleport Ely, Cambridgeshire CB6 1RA

Tel.: +44 (0) 1353 865485 Email: [email protected] Web: www.asynt.com Company Profile A fresh outlook in chemistry technologies

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Asynt was formed in July 2003, the aim being to develop, supply and support new and novel products and services that would become core to the chemist’s future needs. Our concept is to provide completely new solutions for chemists as well as a range of supporting products unique to us. Since inception we have developed the DrySyn range of products (Launched March 2004) as well as successfully introducing our partner company PharmaCore’s custom synthesis

services into the European market. We have a 100% commitment to investing in new products and chemistries and plan to launch new ideas on a regular basis. All of the products we develop are from the chemist’s needs and are developed by real chemists. Our current team has over 25 years of experience between them in providing, developing and supporting novel and new world leading products for chemists.

Biotage Ltd Contact details: Steve Evans Janet Sharp 15 Harforde Court Foxholes Business Park Hertford Hertfortshire SG13 7NW Tel.: +44 (0) 1992 516762 Fax: +44 (0) 1992 501547 Email: [email protected] Web: www.biotage.com Company Profile: Today pharmaceutical chemists throughout the world rely on Biotage products as part of their daily workflow. Data shows that chemists have performed more than 900,000 microwave syntheses and 1.7 million flash purifications using Biotage products. As the innovators of

microwave synthesis technology and cartridge based flash purification, we have set the industry standard for speed, safety and ease of use. The Initiator microwave synthesizer and SP1 flash purification systems from Biotage each perform significant roles in the drug discovery process. Both systems are automated, easily upgradeable to multi-sample capacity, and feature built-in Touch Logic Control for simple and intuitive operation. The Biotage consumable line includes microwave vials and flash chromatography cartridges custom engineered to deliver maximum performance. Biotage has designed four optimum microwave vial sizes allowing chemists the freedom to migrate from milligrams to grams without re-optimization. Biotage FLASH+ cartridges are available in a variety of sizes and media to provide selectivity choices for optimal purifications.

Chemical Computing Group Contact details: Dr Steve Maginn Andrew Henry St Johns Innovation Centre Cowley Road Cambridge CB4 0WS Tel.: +44 (0) 1223 422320 Fax: +44 (0) 1223 422318 Email: [email protected] Web: www.chemcomp.com Company Profile: Chemical Computing Group (CCG) is producer and supplier of the Molecular Operating

Environment (MOE) software for drug discovery. Applications provided within MOE range from protein structure modelling, through structure-based drug design (including pharmacophore derivation and search) and small molecule modelling, to cheminformatics applications such as QSAR, diversity and similarity measures, library design and focusing. Source code for MOE applications is provided to customers, meaning that applications can be customised to meet specific requirements, novel applications constructed, and new ideas tried out and deployed quickly and efficiently, either by customers themselves, or by and with the help of CCG’s support staff.

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Chemspeed Technologies AG Contact details: Brigitte Pichon, Ph.D. Marketing Manager Chemspeed Technologies AG Rheinstrasse 32 CH-4302 Augst Switzerland Tel.: +41 (0) 61 816 95 00 Fax: +41 (0) 61 816 95 09 Email: [email protected] Web: www.chemspeed.com Company Profile: Chemspeed Technologies, headquartered in Augst (Basel), Switzerland, is a global leader in

the development of innovative instruments and consumables for scientists working in research and development laboratories including a line of fully automated parallel synthesizers, instruments for high throughput solid dispensing and liquid handling, and workstations for process research and development. Chemspeed is a premier provider of products and services that reduce time-to-market schedules, increase productivity, and lower costs in research and development. Chemspeed designs, manufactures and customizes products and services to meet industry needs and specific customer requirements, and offers a wide variety of options and enhancements.

ComGenex Inc. Contact details: Michael Bossert Janos Gerencser, Ph.D. 7. Zahony u. H-1031 Budapest Hungary Tel.: +36 1 214 2306 Fax: +36 1 214 2310 Email: [email protected] Web: www.comgenex.hu Company Profile: ComGenex is a dynamic company offering medicinal chemistry and drug discovery services. ComGenex provides technologies allowing its

partners to bridge the gap between genomics/proteomics and novel drug candidates, enabling them to more efficiently focus and accelerate their drug discovery processes. ComGenex employs the latest technlologies to synthesize complex structures and combinatorial libraries, provides unique reagents and challenging intermediates for facilitated chemisrty, as well as comprehensive analytical services. Over the past 13 years, ComGenex has provided creative, sophisticated products and services that have helped the pharmaceutical, agrochemical and biotechnology research industries plan, manage and expedite drug discovery with confidence.

Ilika Technologies Ltd Contact details: Graeme Purdy Centre for Enterprise and Innovation University of Southampton Southampton SO17 1BJ Tel.: +44 23 8059 3095 Email: [email protected] Web: www.ilika.com Company Profile:

Ilika is a science-led materials discovery company using cutting edge high throughput techniques to create and characterise libraries of novel materials. The Company has particular expertise in the creation of new inorganic materials using thin film methodology and the application of polymer science for the invention of novel devices and formulations. Examples of the types of products into which Ilika is researching are fuel cell electrodes, hydrogen storage materials, electronic materials and medical devices.

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IRIS Biotech GmbH Contact details: IRIS Biotech Waldershoferstr. 51 D-95615 Marktredwitz Germany Tel.: +49 9231 9619 73 Fax: +49 9231 9619 99 Email: [email protected] Web: www.iris-biotech.de Company Profile: Escorts you from Grams to Multi-Ton Lots Starting Materials for Peptide and DNA Synthesis IRIS Biotech was established in 2001 as a joint venture of several bulk producers of raw materials for peptide synthesis and is dedicated to starting reagents for Peptide and

Peptidomimetic Synthesis, for Solid Phase Organic Chemistry, and Combinatorial Chemistry: We supply from Grams to Multi-Ton Lots:

• Amino Acid Derivatives, Carbohydrates and Building Blocks

• Organic Intermediates and APIs from mg to multi-tons, Non-GMP and GMP

• Coupling Reagents (HBTU, HCTU and many more)

• Linkers (Rink, Ramage, PAL, PAM), Protecting Groups, Scavengers (DTT)

• Resins and loaded Resins • Products for Life Science Research

(Geldanamycine, Rapamycine) • Reagents and Custom Synthesis

Key Organics Ltd Contact details: Elizabeth Jones Claus Stroander Highfield Industrial Estate Camelford Cornwall PL32 9HA Tel: 01840 212137 Fax 01840 213712 Email: [email protected] Web: www.keyorganics.ltd.uk

Company Profile: Key Organics – Developers and suppliers of the unique and diverse BIONET Intermediates and Screening Libraries are now offering key focused libraries with a dedicated team developing novel compound libraries on an exclusive and non-exclusive basis. Key Organics is also one of the UK’s leading providers of Custom and Contract Chemistry Services to the pharmaceutical, biotechnology and agricultural chemistry sectors worldwide on both ‘Fee for Service’ or ‘Full Time Equivalent’ schemes. To find out more, come along to our stand at the Eurocombi 3 Exhibition where Elizabeth Jones will be delighted to answer your questions.

Merck Biosciences AG Contact details: Christine Wittmer Dr. Sophie Barthélémy Weidenmattweg 4 CH-4448 Läufelfingen Switzerland Tel.: +41 62 285 25 41 Fax: +41 62 285 25 20

Email: [email protected] Web: www.novabiochem.com Company Profile: About us For 20 years Novabiochem® has been the leading provider of state-of-the-art, innovative building blocks, resins, and solid-supported

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reagents for peptide, protein and high-throughput chemical synthesis. Our strength: Know-How and service It is our expertise researchers worldwide rely on when it comes to finding straight forward solutions to their synthetic challenges. New products and applications are advertised through our periodically issued publications, Novabiochem Letters, Innovations, and e-lines.

Our commitment: Providing excellence Doing business with Novabiochem means having a partner who cares about your success. Novabiochem is a brand of Merck Biosciences AG, an affiliate of Merck KGaA, Darmstadt, Germany.

Polymer Laboratories Ltd Contact details: Alasdair MacDonald Essex Road Church Stretton Shropshire SY6 6AX Tel: +44 01694 723581 Fax: +44 01694 722171 Email: [email protected] Web: www.polymerlabs.com Company Profile: Polymer Laboratories (PL) is a world-renowned specialist manufacturer of polymeric particles for synthetic, chromatographic and diagnostic applications, with particular emphasis placed on

product quality and innovation. PL’s StratoSpheresTM range of polymer particles is designed for the solid phase synthesis of medicinal and combinatorial small molecules and peptides. For solution phase synthesis, the StratoSpheres range includes solid supported reagents and scavenger resins in a wide variety of formats. Our resins, polymeric reagents and scavengers offer advantages of high quality, exceptional batch to batch reproducibility and tightly controlled, optimized particle sizes. This provides for improved product quality and increased yields.

Sigma-Aldrich Company Ltd Contact details: Siobhan Marsden Fancy Rd Poole Dorset BH12 4QH Tel.: +44 (0) 7775 666583 Fax: +44 (0) 1202 712245 E-Mail: [email protected] Web: www.sigma-aldrich.com Company Profile: Sigma-Aldrich is a leading Life Science and High Technology company. The Company's biochemical and organic chemical products and kits are used in scientific and genomic research,

biotechnology, pharmaceutical development, the diagnosis of disease and as key components in pharmaceutical and other high technology manufacturing. It has customers in life science companies, university and government institutions, hospitals, and in industry. Over one million scientists and technologists use its products. Sigma-Aldrich operates in 34 countries and has over 6,000 employees providing excellent service worldwide. The Company is committed to the success of its Customers, Employees and Shareholders through leadership in Life Science, High Technology and Service. For more information about Sigma-Aldrich, please visit its award-winning web site at http://sigma-aldrich.com.

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Tessella Support Services plc Contact details: Mark Claxton Paul Munton 3 Vineyard Chambers Abingdon Oxfordshire OX14 3PX Tel.: +44 (0) 1235 555511 Fax: +44 (0) 1235 553301 Email: [email protected] Web: www.tessella.com Company Profile: Tessella specialises in the application of innovative software solutions to scientific, technical and engineering problems. Our services cover software design and development, IT

consultancy, infrastructure support and project management. We are vendor-independent and always offer the solution that is best for our clients. We deliver creative and robust systems including: data acquisition and control, data analysis, database systems, digital archiving, GUIs, internet/intranet applications, modelling and simulation, visualisation/graphics and systems support. We are one of the UK's leading independent suppliers of software solutions to the biotech, pharmaceutical and medical community with extensive experience of LIMS, Informatics and data management systems for High Throughput Technologies.

Wiley-VCH Verlag GmbH & Co. KGaA Contact details: Wiley-VCH Verlag Dr Carina Kniep Boschstr. 12 69469 Weinheim Germany Tel.: +49 (0) 6201 606 308 Fax: +49 (0) 6201 606 184 Email: [email protected] Web: www.wiley.com or www.wileyeurope.com

Company Profile: Founded in 1807, John Wiley & Sons, Inc., is an independent, global publisher of print and electronic products. Wiley specializes in scientific and technical books, journals, textbooks and educational materials for colleges and universities, and professional and consumer books and subscription services. Wiley's Internet Site can be accessed at www.wiley.com or for Europe www.wileyeurope.com. Wiley-VCH is the German subsidary.

Zinsser Analytic UK Ltd Contact details: Howarth Road Maidenhead SL6 1AP Tel.: +44 (0) 1628 773202 Fax: +44 (0) 1628 672199 Email: [email protected] Web: www.zinsser-analytic.com Company Profile: Zinsser Analytic supply sophisticated systems for applications in modern drug discovery, screening and synthesis, and standard laboratory

automation: Our system LISSY 2002 is a fast pipetting station which can be equipped with up to 16 dispensing tips. CALLI is our system for calibrating of vials and weighing of liquid compounds. Our other systems include SOPHAS - High Throughput Synthesiser for over 800 parallel syntheses, NAVIGATOR - microwave synthesis preparation and workup, REDI - automated dry powder and resin dispensing, MOSS - a worldwide accepted system for HTS and CRISSY for polymorph & salt screening studies.

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Delegate list Title First Name Surname Affiliation Country Prof Ernesto Abel-Santos Albert Einstein College of Medicine U.S.A. Dr Rhett Affleck Discovery Partners International U.S.A. Ms Bauke Albada University of Utrecht Netherlands Dr Jesus Alcazar Janssen-Cilag S.A. Spain Prof. Mohammed Al-Sayah American University of Sharjah UAE Mr David Anstee Zinsser Analytic UK Dr Sophie Barthélémy Merck Biosciences AG Switzerland Dr Andrea Basso Università degli Studi di Genova Italy Mr Jörg Bauer University of Tübingen Germany Dr Hartmut Beck Bayer HealthCare Germany Mr Adam Belsom University of Edinburgh UK Mr Gavin Bluck Syngenta UK Mr Michael Bossert Comgenex Hungary Dr Ulrich Bothe Schering AG Germany Prof. Mark Bradley University of Edinburgh UK Dr Karen Brace Ilika Technologies UK Mr Ken Browne Technology Networks Ltd. UK Dr Thomas Bruckdorfer IRIS Biotech GmBH Germany Miss Carole Brückler University of Edinburgh UK Dr Olga Burchak CEA France Prof. Gerardo Byk Bar Ilan University Israel Miss Frederica Catti University of St. Andrews UK Dr Jin Ku Cho University of Edinburgh UK Miss Alessandra Chighine University of Edinburgh UK Ms Polly Child Wiley UK Dr Christian Christensen Carlsberg Laboratory Denmark Mr Mark Claxton Tessella Support Services plc UK Ms Elizabeth Conway GlaxoSmithKline UK Dr David Corens Janssen Pharmaceutica Belgium Dr Stefano Crosignani Serono Pharmaceutical Research Institute Switzerland Mr Tobias Cull University of Edinburgh UK Dr Ferenc Darvas Comgenex Hungary Dr Mike Davies Dr Bimbisar Desai Karl-Franzens-University of Graz Austria Dr Juan José Díaz-Mochón University of Edinburgh UK Mr Frederik Diness Carlsberg Laboratory Denmark Prof. Takayuki Doi Tokyo Institute of Technology Japan Dr Gyorgy Dorman ComGenex Inc Hungary Mr Alan Dowling Syngenta UK Prof. Jonathan Ellman University of Berkeley U.S.A. Mr Steve Evans Biotage Ltd UK Mr Andrew Extance Tripos Discovery Research Ltd UK Mr Martyn Fordham Asynt UK

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Dr Robert Frank German Research Centre for Biotechnology Germany Dr Henrik Franzyk The Danish University of Pharmaceutical

Sciences Denmark

Dr Yukari Fujimoto Osaka University Japan Prof. Koichi Fukase Osaka University Japan Mr Luciano Galveia University of Edinburgh UK Dr David Gammie Tessella Support Services plc UK Janos Gerencser ComGenex Inc. Hungary Mr James Glynn Tessella Support Services plc UK Mr Peter Greenhalgh Astech Projects UK Dr Hubert Gstach Novartis Austria Mrs Annika Gustavsson Karo Bio AB Sweden Nina Hall Technology Networks Ltd. UK Mr Mikkel Harndahl Panum Institute, IMMI Danemark Nick Hathway Sigma-Aldrich Company UK Prof. Brian Hayden University of Southampton UK Dr Jean-Michel Henlin Institut de recherches Servier France Dr Peter Heesterman Tessella Support Services plc UK Dr Thomas Hoeg-Jensen Novo Nordisk Denmark Mr Lawrence Hopkins Tessella Support Services plc UK Mr Yusuke Iijima Tokyo Institute of Technology Japan Prof. Klavs Jensen M.I.T. U.S.A. Dr Steve Jordan Argonaut Technologies UK Elizabeth Jones Key Organics Ltd UK Dr Günther Jung University of Tuebingen Germany Prof. Oliver Kappe Karl-Franzens-University Austria Mr Tuomas Karskela University of Turku Finland Ms Johanna Katajisto University of Turku Finland Dr Mark Kerry Evotec UK Dr Carina Kniep Wiley UK Dr Michael Krusche Activotec Ltd UK Prof. Olivier Lavastre Centre for Innovation and Technologies France Mr Sebastian Le Quement Carlsberg Laboratory Denmark Dr Christopher Lee Ilika Technologies UK Miss Gersande Léna CNRS, Strasbourg France Ms Marika Leppänen University of Turku Finland Mr Albert Liberski University of Edinburgh UK Michael Ling Ilika Technologies UK Mr Chris Littlewood Activotec Ltd UK Prof. Harri Lonnberg University of Turku Finland Mr José María López Pedrosa University of Edinburgh UK Mr Yucheng Luan University of Edinburgh UK Mrs Jing Ma University of Edinburgh UK Dr Alasdair MacDonald Polymer Labs U.S.A. Dr Steve Maginn Chemical Computing Group UK Prof. Wilhelm Maier Universitaet des Saarlandes Germany Ms Siobhan Marsden Sigma-Aldrich Company UK

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Dr Andreas Marzinzik Novartis Pharma AG Switzerland Dr Farah Mavandadi Biotage Ltd U.S.A. Dr Lieven Meerpoel Janssen Pharmaceutica Belgium Prof. Morten Meldal Carlsberg Laboratory Denmark Dr Beatrix Merla Gruenenthal GmbH Germany Prof. Scott Miller Boston College U.S.A. Mr Phillip Milnes University of Edinburgh UK Dr Maxim A. Mironov Urals State Technical University Russia Dr Stifun Mittoo University of Southampton UK Dr Antoni Molins Almirall Prodesfarma S.A. Spain Dr Claire Mormiche Ilika Technologies UK Mr Paul Munton Tessella Support Services plc UK Dr Vince Murphy Symyx Technologies, Inc. U.S.A. Dr Thomas E. Nielsen Carlsberg Laboratory Denmark Dr John Okonya Sanofi-Aventis U.S.A. Dr Christian A. Olsen The Danish University of Pharmaceutical

Sciences Denmark

Dr Patrick Page Serono Pharmaceutical Research Institute Switzerland Prof. Anna Maria Papini University of Florence Italy Prof. Tamás Patonay University of Debrecen Hungary Dr Elisa Peroni University of Florence Italy Miss Silvia Pereira Technical University Delft Netherlands Mr Songsak Planonth University of Edinburgh UK Mr Christophe Portal University of Edinburgh UK Miss Delphine Pouchain University of Edinburgh UK Dr Maurizio Pulici Nerviano Medical Sciences Italy Mr Graeme Purdy Ilika Technologies UK Prof. Jörg Rademann University of Tuebingen Germany Dr Sunil Rana Biotage, Argonaut Technologies UK Dr Wolfgang Rapp Rapp Polymere Germany Mr Philippe Ratel Laboratoires Fournier France Prof. Jean-Louis Reymond University of Berne Switzerland Dr Rosario Sanchez Martin University of Edinburgh UK Mr James Salter Arrow Therapeutics Ltd UK Dr Jens Scheidtmann University of Saarland Germany Dr Thomas Schwalbe Microreactor Systems Provider U.S.A. Mr Gianluca Sechi University of Edinburgh UK Prof. Peter Seeberger Swiss Federal Institute of Technology Switzerland Dr Jan-Marcus Seifert Novartis Institutes for Biomedical Research Austria Prof. Pierfausto Seneci University of Milan Italy Mrs Janet Sharp Biotage Ltd UK Dr Leo Sliedregt Solvay Pharmaceuticals Netherlands Dr Francesco Spadola Polymer Laboratories France Dr Magda Stankova Sanofi-Aventis U.S.A. Claus Stroander Key Organics UK Dr Andy Sutherland CEAC, Aston University UK Mrs Lorena Taboada Lilly S.A Spain

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Prof. Takashi Takahashi Tokyo Institute of Technology Japan Dr Patrick Tielmann Boehringer Ingelheim Pharma Germany Mr Guilhelm Tourniaire University of Edinburgh UK Dr Josef Vagner University of Arizona U.S.A. Mr Eric Valeur University of Edinburgh UK Dr Wim Van Den Nest DiverDrugs, SL Spain Prof. Erik Van der Eycken University of Leuven Belgium Prof. Johan Van der Eycken Ghent University Belgium Mrs Annick Vancolen IRIS Biotech GmbH Germany Dr Ken Veal InsightFaraday UK Mr Dieter Verzele Ghent University Belgium Dr Mythily Vimal GlaxoSmithKline UK Mr Robert Walker Tessella Support Services plc UK Dr Jassy Wang Industrial Technology Research Institute Taiwan Prof. Helma Wennemers University of Basel Switzerland Dr Nicholas Westwood University of St Andrews UK Mr Robert Wheeler GlaxoSmithKline Pharmaceuticals UK Mr Dieter Wiedenmayer Boehringer Ingelheim Pharma Germany Dr Claudia Wittland Gruenenthal GmbH Germany Mrs Christine Wittmer Merck Biosciences AG Switzerland Mr Kasper Worm-

Leonhard Carlsberg Laboratory Denmark

Dr Bi-Chu Wu ITRI Taiwan Ms Susana Yenes Laboratorios Dr. Esteve, S.A. Spain

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Acknowledgements

We would like to thank

The Local Organising Committee

The Scientific Committee

Winchester University College

The invited speakers

Our Sponsors:

Chemical Computing Group

CombiChem.net

Comgenex

HighTroughputExperimentation.com

Ilika

Johnson and Johnson Pharamceutical R&D

Novartis

Polymer Laboratories

and You as the participants

for making Eurocombi3 a success!

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eurocombi3 – winchester 18 to 23 july 2005eurocombi3 – winchester 18th to 23rd july 2005 3rd...

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