Bioorthogonal Reactions

Bioorthogonal Reactions：Outline

Part I. Key Concepts: Definition, Method, and Scope

Part II. Bioconjugation: Bioorthogonal Reactions

Part III. Applications: ADC Drug

Bioorthogonal Reactions：Outline

Part I. Key Concepts: Definition, Method, and Scope

Part II. Bioconjugation: Bioorthogonal Reactions

Part III. Applications: ADC Drug

Bioorthogonal Reactions：Definition

ACCOUNTS OF CHEMICAL RESEARCH ’ 666–676 ’ 2011 ’ Vol. 44, No. 9

Bioorthogonal Reactions：Features

ACCOUNTS OF CHEMICAL RESEARCH ’ 666–676 ’ 2011 ’ Vol. 44, No. 9

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Bioorthogonal Reactions：Features

(A)Introduction and immobilization of the reporter inside a living cell by genetic, metabolic, affinity based, or other means.

(B)Labeling of the immobilized reporter with a reactive probe bearing a detection tag by a bioorthogonal ligation reaction.

(C)Revelation of the detection tag by ananalytic method such as microscopy, gel electrophoresis, pull down, and so forth.

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Bioorthogonal Reactions：Features

1. High selectivity: They have to be highly selective in order to specifically label only the intended target and minimize background labeling in a vastly diverse biological environment.

2. Biocompatiblity: Meaning that it has to work at physiological conditions and no toxic component must be present.

3. Kinetics: The reaction kinetics has to be favorable so that the ligation occurs before the reaction partners can be cleared from the biological system.

4. Stability: Their products and educts have to be inert and remain stable toward any unwanted biological or chemical reactions.

5. Accessibility: The functional groups for the ligation reaction have to be as small as possible and should be readily available to enable the incorporation into biomolecules.

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Bioorthogonal Reactions：Key Elements

1. Biological Target: Peptides and Proteins, Carbohydrates, Nucleic Acids, Lipids.

2. Chemical Reporters : Ketone, Azide, Alkyne, Alkene, Aryl Halide, Alkene......(extrinsic)

2. Probes or Tags : Fluorophore, Biotin, Polymer, Drug......

3. Reactions：Aldehyde/Ketone Condensation, Staudinger Ligation, 1,3-Dipolar Cycloaddition,

Strain-Promoted Azide-Alkyen Cycloaddition, Diels-Alder Reaction......

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Bioorthogonal Reactions：Method and Scope

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Installing functionality into target biomolecules

Bioorthogonal Reactions：Method and Scope

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Installing functionality into target biomolecules

Chemical Modification

Enzymatic tagging

Unnatural amino acid mutagenesis

Bioorthogonal Reactions：Method and Scope

Diazo Transfer

Chemical Modification

Chemoselective and Bioorthogonal Ligation Reactions, Volume 1, 98-101, WIELY VCH

Bioorthogonal Reactions：Method and Scope

NATURE METHOD, VOL.2 NO.2, FEBRUARY 2005 99-104

Enzymatic tagging

Bioorthogonal Reactions：Method and Scope

Unnatural amino acid mutagenesis

Nature Reviews Molecular Cell Biology volume13, pages168–( )

Bioorthogonal Reactions：Method and Scope

Unnatural amino acid mutagenesis

Lehninger Principles of Biochemistry, Sixth Edition, 1119 1121

Bioorthogonal Reactions：Method and Scope

Unnatural amino acid mutagenesis

Lehninger Principles of Biochemistry, Sixth Edition, 1119 1121

Bioorthogonal Reactions：Outline

Part I. Key Concepts: Definition, Method, and Scope

Part II. Bioconjugation: Bioorthogonal Reactions

Part III. Applications: ADC Drug

Bioorthogonal Reactions：Method and Scope

dx.doi.org/10.1021/bc500028d | Bioconjugate Chem. 2014, 25, 82

Reactions and Revelation

ReactionsRevelation

Bioorthogonal Reactions：Cycloaddition

Copper Catalyzed Azide-Alkyne Cycloaddition

[3+2]-Dipolar Cycloadditions

1963，Huisgen discover the 1,3-dipolar cycloaddition reaction between azides and acetylenes.

2001，Sharpless group and Meldal group reported the first catalytic CuAAC.

Bioorthogonal Reactions：CycloadditionCopper Catalyzed Azide-Alkyne Cycloaddition (CuAAC)

http://tmedweb.tulane.edu/pharmwiki/doku.php/aspirJ. Am. Chem. Soc. 2013, 135, 14568−14573

Bioorthogonal Reactions：CycloadditionStrain Promoted Azide Alkyne Cycloaddition (SPAAC)

Bioorthogonal Reactions：CycloadditionStrain Promoted Azide Alkyne Cycloaddition (SPAAC)

Bioorthogonal Reactions：CycloadditionStrain Promoted Azide Alkyne Cycloaddition (SPAAC)

Imaging glycans in vivo

Bioorthogonal Reactions：CycloadditionStrain Promoted Azide Alkyne Cycloaddition (SPAAC)

Imaging glycans in vivo

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Normal Electron Demand Diels−Alder and Inverse Electron Demand Diels−Alder

Bioconjugate Chem. 2014, 25, 825−8

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Normal Electron Demand Diels−Alder

Bioconjugate Chem. 2014, 25, 825−8

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Inverse Electron Demand Diels−Alder

Bioconjugate Chem. 2014, 25, 825−8

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Inverse Electron Demand Diels−Alder

Bioconjugate Chem. 2014, 25, 825−8

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Inverse Electron Demand Diels−Alder

Bioconjugate Chem. 2014, 25, 825−8

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Inverse Electron Demand Diels−Alder

Bioconjugate Chem. 2013, 24, 1210−1

Bioorthogonal Reactions：Cycloaddition[4 + 2] cycloadditions

Inverse Electron Demand Diels−Alder

Angew. Chem. Int. Ed. 2012, 51, 7752

Bioorthogonal Reactions：Cycloaddition

ACS Chem. Biol. 2014, 9, 592−6

Bioorthogonal Reactions： Staudinger Ligation

ACS Chem. Biol. 2014, 9, 592−6

Nontraceless Staudinger Ligation

Bioorthogonal Reactions： Staudinger Ligation

ACS Chem. Biol. 2014, 9, 592−6

Traceless Staudinger Ligation

Bioorthogonal Reactions： Staudinger Ligation

NATURE | VOL 430 | 19 AUGUST 2004

Bioorthogonal Reactions： Staudinger Ligation

NATURE | VOL 430 | 19 AUGUST 2004

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions

NATURE CHEMISTRY | VOL 3 | MARCH 2011 |

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions-Pd0-mediated allylcarbamate cleavage

NATURE CHEMISTRY | VOL 3 | MARCH 2011 |

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions-Suzuki Reaction

NATURE CHEMISTRY | VOL 3 | MARCH 2011 |

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions-Heck Reaction

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions-Heck Reaction

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： MISCELLANEOUS LIGATION REACTIONS

Palladium Catalyzed Coupling Reactions-Sonogashira Reaction

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： Summary

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： Summary

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： Summary

J. Am. Chem. Soc. 2011, 133, 15870–1

Bioorthogonal Reactions： Summary

Bioorthogonal Reactions：Outline

Part I. Key Concepts: Definition, Method, and Scope

Part II. Bioconjugation: Bioorthogonal Reactions

Part III. Applications: ADC Drug

Bioorthogonal Reactions： ADC Drug

NATURE CHEMISTRY | VOL 8 | FEBRUARY 2016

Bioorthogonal Reactions：ADC Drug

NATURE CHEMISTRY | VOL 8 | FEBRUARY 2016

Bioorthogonal Reactions：ADC Drug

NATURE CHEMISTRY | VOL 8 | FEBRUARY 2016

Bioorthogonal Reactions：ADC Drug

http://xdrug.dxy.cn/bbs/topic/36716245?source=

Bioorthogonal Reactions：ADC Drug

http://xdrug.dxy.cn/bbs/topic/36716245?source=

Bioorthogonal Reactions：Reference

1. Finding the Right (Bioorthogonal) Chemistry, ACS Chem. Biol. 2014, 9, 592−605

2. Developments in the Field of Bioorthogonal Bond Forming Reactions Past and Present Trends, Bioconjugate Chem. 2014, 25, 825−839

3. From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions, ACCOUNTS OF CHEMICAL RESEARCH ’ 666–676 ’ 2011 ’ Vol. 44, No. 9

4. Recent advances in the construction of antibody–drug conjugates, NATURE CHEMISTRY | VOL 8 | FEBRUARY 2016 |

5. Chemoselective and Bioorthogonal Ligation Reactions Concepts and ApplicationsEdited by W. Russ Algar, Philip E. Dawson and Igor L. MedintzVolume 1

Bioorthogonal Reactions

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