Tetrahedron Letters 57 (2016) 5540–5550

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Tetrahedron Letters

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Digest paper

Non-standard amino acids and peptides: From self-assembly tonanomaterials

http://dx.doi.org/10.1016/j.tetlet.2016.11.0220040-4039/� 2016 Elsevier Ltd. All rights reserved.

⇑ Corresponding author.E-mail address: sara.pellegrino@unimi.it (S. Pellegrino).

Francesca Clerici, Emanuela Erba, Maria Luisa Gelmi, Sara Pellegrino ⇑Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy

a r t i c l e i n f o

Article history:Received 22 July 2016Revised 26 October 2016Accepted 4 November 2016Available online 5 November 2016

Keywords:Non-standard amino acidsPeptidesNanomaterialsSelf-assembly

a b s t r a c t

The exploitation of peptides in the development of smart nanomaterials is gaining increasing attention inthe last few years. Amino acids are indeed able to drive the self-assembly and the self-organization at themolecular level. By using non-standard amino acids, it is possible to expand the scope of the possibleapplications, ranging from biomaterials, biosensors to drug delivery systems. In this digest, the recentadvances in this field are presented.

� 2016 Elsevier Ltd. All rights reserved.

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5540Capped natural amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5541Non standard a-amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5542

Linear a-amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5542Cyclic a-amino acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5544

b-Amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5546

Linear b-amino acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5546Cyclic b-amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5547

c-Amino acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5548Cyclopeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5549Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5549References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5550

Introduction

Amino acids are the building blocks of peptides and proteins. Inmillion years of evolution, Nature has optimized their structures toabsolve numerous functions in almost all the biological processes.They are indeed able to induce a high molecular complexity start-ing from relatively simple molecules, being at the molecular basisof the living world. Taking inspiration from Nature, scientists arenow trying to develop smart peptide materials for a wide range

of applications, such as biomolecular devices, biosensors, andhybrid catalysts. The modularity of amino acids and their abilityat driving self-assembly and self-organization leads to a high ver-satility in functions. Amino acids can both function as single mole-cules and when inserted in peptides. Furthermore, by tailoring thefunctional groups on the side chains and at the N- and C-terminusit is possible to expand endlessly their molecular variability. Differ-ent kinds of materials could be thus developed, and, depending onthe solvent and the environmental conditions, hydro- and organo-gel, nanoarchitectures, vesicles and micelles have been obtained. Inthe case of standard or coded amino acids, many papers, somereviews and books have recently been published.1 In this digest,

Fig. 1. Examples of non-standard amino acids and nanomaterials developed.

F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550 5541

we aimed to explore the advances in using non-standard aminoacids for the design of nanomaterials, highlighting in particularsome new developments which have been reported since 2010. Acomprehensive review of all obtained peptide nanostructures isbeyond the scope of this manuscript. We focused our attentionon the different amino acid features, starting from simple variationat N- and C-terminus of standard amino acids to unnatural a, b andc-amino acids. We envisaged the use of non-coded amino acids tobe of particular relevance, expanding the scope of the nanoarchi-tectures so obtained. In particular, the use of non-coded amino

N

N

O O

OON

N OO

OO

NDI PDI

R CO2H

CO2HR

R CO2H

CO2HR

Fig. 3. N-Arylenediimides derivatives of single amino aci

Fig. 2. Naphtalene funct

acids opens the doors to more stable materials that could be, forinstance, exploited in biomedical applications such as drug deliv-ery systems (See Fig. 1).

Capped natural amino acids

A simple and widely used strategy to modify the amino acidscaffold is the introduction of substituents at N- or C-terminus.2

The most common functionalization is the attachment of an aro-matic moiety, such as pyrene3 and ferrocene4, through amide bondformation. In these examples, p–p interactions drive the self-assembly of the constructs yielding, in most cases, hydrogelators.Naphthalene group has been used to functionalize dendronscomposed of aspartic acid (Asp) and alanine (Ala), (Nap-G1 andNap-G2, Fig. 2).5

Nap-G1 in cyclohexane develops a gel, formed by a fibrous net-work with b-sheet architecture, but in mixed solvents (chloroform/petroleum ether 1:5, v/v) exhibits a spherulitic network (Fig. 2). Onthe other hand, Nap-G2 acts as an efficient organogelator in chlo-roform but forms crystalline microbelts in relatively high polaritysolvents, such as acetone and methanol (Fig. 2). These polymorphicfeatures are due to the bulky naphthyl group at the N terminus thatdrives the molecular architectures formation during the self-assembly in different solvents.

The derivatization of amino acids with arylenediimides has alsobeen investigated. Particularly, naphthalenediimides (NDIs) andperylenediimides (PDIs) (Fig. 3) give access to a wide variety ofapplications ranging from biomedicine to electronics, as reviewed

N

O

OO

HN CO2Me

BPI-FF

ds (NDI and PDI) and of Phe-Phe dipeptide (BPI-FF).

ionalized dendrons.

5542 F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550

in 2012.6 For example, Ala forms spiral nanorings, while Phe nano-spheres. Several papers related to their use in the field of molecu-larly engineered organization, hydrogelators, host-guestinteractions, dynamic combinatorial chemistry, molecular recogni-tion, photosystems and biomedical applications have been pub-lished more recently.7

The aromatic dipeptide Phe-Phe, which is known to be the min-imal self-assembling peptide sequence, has been functionalizedwith benzo[ghi]perylene monoimide (BPI-FF, Fig. 3) showing opti-cal behavior and self-assembly in different organic solvents.8

Few examples dealing with C-terminus functionalization arereported. Stilbene derivatives of Phe-Phe dipeptides (STL-FF,Fig. 4) self-assemble in various organic solvents to form an organo-gel. Interestingly, due to the cis–trans conformational isomeriza-tion of the double bond, the organogel is photoresponsive and agel–sol transition occurs by irradiating the gel with UV light at365 nm.9

An interesting class of N-substituted amino acids is obtained bythe reduction of the corresponding Schiff bases to N-aryl deriva-tives (Fig. 5).10 These compounds have been used for the prepara-tion of Coordination Polymers (CPs) or supramolecular assembliesof CuII under non-hydrothermal conditions. In particular, the pres-ence or absence of a coordinated water molecule in the metal–li-gand complex is responsible for the formation of supramolecularassemblies over CPs.

H3COOCNH

ONH

ONHBoc

STL-FF

Fig. 4. C-Stilbene substituted Phe-Phe dipeptide.

O

OHHN

HO

O

OHHN

R2R1

R2

R1= H, OH

R2= Ph, Het

Fig. 5. N-Aryl derivatives.

Fig. 6. FESEM images of xerogels prepared by freeze drying the corresponding gels. (A(25 g L�1); (D) click-Glu in CHCl3 (100 g L�1). (From Bachl J, et al. Chem Commun, 2015,

Novel supramolecular soft gel materials were prepared exploit-ing the triazole isosteric substitution of peptide amide bond.Disubstituted 1,2,3-triazoles are indeed known as powerful non-classical isosters of amides as they can mimic either a trans- or acis-configuration of the amide bond depending on the substitutionpattern of the triazole (1,4- or 1,5-, respectively). This replacementhas been widely used in medicinal chemistry for the rationaldesign of new drugs. Interestingly, the isosteric replacement para-digm has been now transferred from medicinal chemistry to softmaterials. Taking inspiration from N-stearoyl-L-glutamic acid(C18-Glu,) which is known to self-assemble in many solvents atsuitable concentrations, the analogue click-Glu can be easily syn-thesized via click chemistry by the copper(I)-catalyzed azide–alkyne cycloaddition.11 Isosteric gelators C18-Glu and click-Glugive a variety of physical hydrogels/organogels with different ther-mal, mechanical, morphological and diffusional properties (Fig. 6).In particular, click-Glu revealed better gelator performance inpolar protic solvents, whereas C18-Glu exhibited improved proper-ties in non-polar ones. These systems have been successfullyapplied for fine-tuning the release of the antibiotic vancomycin.

Non standard a-amino acids

A large number of non-standard a-amino acid, i. e. amino acidsin which the side chain is modified with respect to natural ones,have been synthesized in the last few years.12 Nevertheless, theirapplication in nanomaterials preparation, both as single moleculesand when inserted in peptides, has still not been completelyexploited even if there has been an increase in their use whichcan be seen from literature.

Linear a-amino acids

Non-coded linear amino acids are able to self-assemble on dif-ferent type of metal nanoparticles (gold, silver, platinum. . .). Asan example, a-methyl L-cysteine (aMe-L-Cys, Fig. 7) has been usedfor decorating gold and silver nanoparticles (NPs).13 The gold NPs

) C18-Glu in H2O (25 g L�1); (B) C18-Glu in CHCl3 (100 g L�1); (C) click-Glu in H2O51, 5294–5297).

H2N CO2H H2N CO2H

Abu Nva

H2NCOOH

HS

αMe-L-Cys

Fig. 7. Examples of linear non standard a amino acids.

H2N CO2H H2N CO2H H2N CO2H

ΔPhe ΔAbu ΔAla

Fig. 8. Examples of linear dehydro a-amino acids.

H2N CO2H

NNN N

pazoDbg

Fig. 10. pAzoDbg a-amino acid.

F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550 5543

show higher aqueous stability against aggregation in comparisonwith the nanoparticles capped with unmodified L-cysteine. Suchprevention of coalescence is due to the conformational restrictionimposed by the a-methyl group, which affects the organizationof the amino acid with respect to both the gold surface and theneighboring molecules. On silver nanoparticles, significantly loweradsorbed molecules of aMe-L-Cys than for cysteine itself, wasobserved. Apparently, the small variation in structure causes a sub-stantial change in optical activity of the systems. This unexpectedbehavior could be due to steric hindrance of an additional methylgroup that does not allow 3D supramolecular structures to beformed on nanoparticles surface.

Dipeptides containing hydrophobic side chains are an excep-tional source of microporous organic materials, although thereare few examples of compounds composed of non standard aminoacids. Gorbitz and coworkers reported several new dipeptides con-taining non-proteinogenic L-2-aminobutanoic acid (Abu, Fig. 7)and/or L-2-aminopentanoic acid (Nva, Fig. 7).14 These dipeptidescrystallize in permanently porous architectures characterized byparallel and independent chiral channels with distinct diametersand helicities. Interestingly, through the fine-tuning of the channelcross-section by systematically changing the amino acid sidechains, the empty space can be exploited for accommodatingguests.

Dehydrodipeptides, i. e. dipeptides containing dehy-droamino acids, such as dehydrophenylalanine (DPhe, Fig. 8),

HN

O

NH O

HN

O

O

O

OBn

OBn

O

OBocHN

NN

A4

O

OBn

H2N CO2H

N N

trans-azoPhe

hν

Fig. 9. Examples of a

dehydroaminobutyric acid (DAbu, Fig. 8), and dehydroalanine(DAla, Fig. 8) have been used for preparing protease resistanthydrogelators functionalized with the nonsteroidal anti-inflamma-tory drug naproxen.15 These hydrogels consist of networks ofmicro/nanosized fibers formed by peptide self-assembly throughstacking interactions of naproxen aromatic groups. Furthermore,the planar geometry of dehydroamino acids and the presence ofsubstituents at the b carbon (DPhe and DAbu), impart rigidity tothe dipeptides, stabilizing the conformation and inducing proteasestability.

A very interesting application takes advantage of the incorpora-tion of photoswitching molecules into molecular building blocks.This creates the possibility of obtaining photoresponsive materialsin which the self-assembled architecture or self-assembling pro-cess can be controlled by the external light stimuli. Among thephotoswitching molecules, azobenzene has been used most widelyby virtue of the large photoinduced changes in its molecular geom-etry and physical properties. Several a-amino acids bearing side-chain azobenzene moieties, such as azo-Phe and other derivatives(e.g. azo-Dbg, A4 and bis-A4) have been used for this purpose(Figs. 9 and 10).16 It has been demonstrated by density functionaltheory calculations that Azo-Phe adopts different conformationsdepending on the cis/trans conformation of the azo-function.16c Inthe case of cis isomer, water tends to stabilize the helical

HN

O

NH O

HN

O

O

O

OBn

OBn

O

O

OBn

ONH

Boc

NN

HNBoc

O

NH

OBnO

O

HN

O

OBn

O

NH

O

OO

OBn

bis-A4

H2N CO2H

N N

cis-azoPhe

zo-Phe peptides.

5544 F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550

backbone arrangement. This conformation is sterically forbiddenfor the trans one that thus adopts a b conformation. Azo-Phe hasbeen introduced in low-molecular-weight (LMW) peptides thatwere used for the preparation of multistimuli-responsivesupramolecular gels. Interestingly, the azobenzene residue can beused as a versatile regulator to reduce the critical gelationconcentration and enhance both the thermal stability andmechanical strength of the gels.

pAzo-Dbg, an a,a-disubstituted aminoacid bearing two azoben-zene moieties covalently linked to the glycine a-carbon atomthrough a methylene group (Fig. 10), has been used to create inter-esting supramolecular systems.

As an example, pAzo-Dbg has been used for substituting aphenylalanine moiety in Phe-Phe dipeptide retaining its self-assembly behavior. The presence of pazo-Dbga-amino acid is par-ticularly profitable, because: 1) the two side-chain azobenzenemoieties give rise to aromatic stacking interactions strong enoughto drive the self-assembly process; 2) these interactions can be dis-rupted by light, thus rendering the supramolecular structure pho-toresponsive. The nanoarchitectures indeed undergo multiple,reversible isomerizations in a variety of solvents upon irradiationwith Vis light (450 nm) or UV light (350 nm). Furthermore, theyare able to load metal nanoparticles (Au, Ag and Pt nanoparticles)retaining the reversible photoswitching properties.17

The non-coded amino acid thienylalanine (Thi) has been used inthe development of polypeptides with conductivity properties,arising from the creation of extended conjugated electronic sys-tems.18 The (2-Thi)(2-Thi)VLKAA sequence, in which the pheny-lalanine residues (F) are replaced by 2-Thi units, was designedand synthesized taking inspiration from AAKLVFF amyloid motif(Fig. 11). b-2-Thienylalanine (2-Thi) residue is expected to conferinteresting electronic properties due to charge delocalization andp-stacking. The peptide is shown to form b-sheet-rich amyloid

S

H2NO

HN

S

O

NH O

HN

O

NH

NH2

O

HN

O

NH

COOH

(2-Thi)(2-Thi)VLKAA

Fig. 11. Chemical formula of (2-Thi)(2-Thi)VLKAA peptide.

Fig. 12. Self-assembly of mixed Pro d

fibrils with a twisted morphology, in both water and methanolsolutions at sufficiently high concentration. The molecular dynam-ics simulations on these systems revealed well-defined foldedstructures (turn-like) in dilute aqueous solution, driven by self-assembly of the hydrophobic aromatic units, with charged lysinegroups exposed to water.

Cyclic a-amino acids

There are a few examples of nanostrucures involving cyclic a-amino acids, most of them exploiting 4-substituted prolines. Thepresence of ring constraints is indeed extremely efficient in stabi-lizing specific secondary structure of the peptides and thus in driv-ing the self-assembly.

Dipeptides containing 4-F or 4-OH prolines, and cyclic a-substi-tuted and/or a,a-disubstituted amino acids self-assemble intooctameric [2]-catenanes (Fig. 12).19 Using dynamic combinatorialchemistry, mixtures of dipeptide monomers were combined toprobe how the structural elements affect the equilibrium stabilityof self-assembled [2]-catenanes versus competing noncatenatedstructures. The catenanes are stabilized by a combination of intra-and inter-macrocyclic hydrogen bonds, multiple aromatic interac-tions, and CH-p interactions. The core structure has been evi-denced as being especially important, as well as b-turnconformation that is the critical feature predicting stability.

Unnatural 4-azido proline has been used for the preparation ofdifferent classes of hybrid nanomaterials.20 The presence of azidogroup, indeed, allows Pro-functionalization with different chemicalentities, through click reaction.

Wennemers et al. exploited 4-azido proline for the develop-ment of collagen derivatives, introducing in the triple helix variousfunctionalities such as carbohydrates (Fig. 13).20a They observedthat the conformational stability of the functionalized collagensdepends on the position of the substituents. Sterically demandingsubstituents should be attached to (4R)-configured amidoprolinesin the Xaa position or to (4S)-configured amidoprolines in theYaa position.

The same research group reported the click conjugationbetween azido functionalized oligoprolines and sterically demand-ing perylenemonoimides (PMIs).20b The so obtained hybridmaterials form worm-like hierarchical supramolecular self-assemblies, via bundles of rigid fibers to nanosheets andnanotubes (Fig. 14). The spatial orientation between p systemsdirectly triggers the self-assembly, allowing a fine tuning ofsupramolecular aggregation.

ipeptides to octameric catenanes.

NAc

O

N

O

N

O

NH2n

NNN

O O

OOO

OEt

n

O Et

OEt

n

n

Fig. 15. Polyproline dendrons.

NH

CO2HR

RR = H, OMe, OEt, Het

HN

O

OHL-spinaTIC

Fig. 16. Examples of cyclic non

Fig. 13. Functionalized collagen derivatives.

Fig. 14. Hybrid collagens from 4-azido proline a) General structure of oligoproline-PMI conjugates. b) Model of the supramolecular organization, front view (left) andside view (right). (From Lewandowska U, et al. Chem Eur J, 2016, 22, 3804).

F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550 5545

Thermoresponsive polyproline dendrons have been obtained bygrafting azido-polyproline to oligo(ethylene glycol) (OEG) poly-mers (Fig. 15).20c The arrangement of the dendrons along thepolyproline backbone influences both the helical propensity andthe thermally-induced phase transitions. Polyprolines carryingone OEG in every three proline moieties adopt PPI conformationin aqueous conditions; however, polyprolines with reducednumber of OEGs, adopt a stable PPII conformation.

1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acids (TIC, Fig. 16)have been used for preparing new simple hydrogelators allowingthe in situ formation of Pt and Ir nanocrystals.21 The Pt nanocrystalswere successfully used as a catalyst for hydrogenation of the nitrogroup.

Another example of application of a cyclic amino acid wasreported by Pedone and coworkers.22 In this work, authorsdescribe the synthesis of a novel nucleoamino acid based on a

L-spinacine residue bearing the DNA nucleobase thimine anchoredto its N-a (Fig. 16). The investigation of the self-assembly proper-ties of the novel nucleoamino acid, lead to important informationon the assembly of supramolecular networks based on the peptidylnucleoside analogue. From UV and LS studies it has been possibleto demonstrate that these structures change as a result of the inter-action with metal ions (Cu2+). Furthermore, by experiments withfresh human serum, the enzymatic stability of the novel peptidylnucleoside analogue was also demonstrated.

In 2012,Gatto and co-workers developedanovelmethod tobuildpeptide self-assembledmonolayers (SAMs) ongoldnanoparticles byexploiting exclusively helix—helix macrodipole interactions.23 Apeptide was prepared containing Ca,a-disubstituted amino acids

NH

NN

NH

N

O

OH

O

N

HNO O

cine Nucleo-spinacine

-standard a-amino acids.

COOH

NH2

H2N COOH

NH

Api

N

COOHH2N

O

oxo-Azn NRB

R OH

Fig. 17. Examples of cyclic a,a disubstituted amino acids.

Fig. 18. Self-assembly of NRB containing peptides.

Fig. 19. Degarelix analogues.

H2NCO2H H2N

CO2H

RH2N

CO2HR

β-alanine β2-amino acid β3-amino acid

H2NCO2H

R

R'

β2,3-amino acid

Fig. 20. Nomenclature of b-amino acids.

5546 F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550

such as a-aminoisobutyric acid (Aib), 4-aminopiperidine-4-carboxylic acid (Api, Fig. 17) and Ca-methyl norvaline (L-(aMe)Nva) residues, and bearing a 1-pyrenyl (Pyr) unit in the proximityof the N-terminus. This peptide generates a stable supramolecularnanostructure where the pyrenylpeptide is incorporated into theSSA4WApalisade.More recently,Oxo-Azn, aa,a-disubstituted con-strained glutamine analogue containing the azepino ring (Fig. 17),has beendesigned to decorate goldnanoparticles througha covalentlinkage.24 Interestingly, Oxo-Aznwas also able to stabilize 310 helixstructure in ultra-short peptide.

Non-proteinogenic norbornene amino acid (NRB, Figs. 17 and18) has been inserted in short peptides containing alanine andAib that are able to form supramolecular assembly of sphericalshapes in water. These nanoaggregates are stable in fetal bovineserum.259470390-2740025.

Non-coded cyclic amino acids have been used for the prepara-tion of spherical nanostructures as drug delivery systems. As anexample, a study has been made on the influence on peptideself-assembly of the amino acid residue at position 7 of Degarelix,a gonadotropin-releasing hormone (GnRH) peptide antagonist(Fig. 19).26 Peptides containing a C a,a-tetrasubstituted amino

acids (such as Acc3, Acc5, Acc6, Fig. 19) are able to form stablevesicles and act as long active compounds.

b-Amino acids

b-Amino acids are commonly considered as unnatural aminoacids, although some representatives of this class occur in natureas secondary metabolites or as components of complex naturalproducts. With respect to a-amino acids, b-amino acids are charac-terized by an additional carbon atom between the carboxylic andamine functionalities. In the presence of substituents, the twoobtained regioisomers are called b2 and b3-amino acids (Fig. 20)

Peptides containing b-amino acids are stable to proteolyticdegradation and present a great chemical variability that leads tothe formation of different and complex secondary structures. Thesemolecular architectures are often able to self-assemble and havebeen exploited in different nanomaterial applications. In particular,their metabolic stability is particularly profitable for drug deliverysystems. Reviews dealing on the different geometries derivingfrom the self-assembly of b-peptides have been recentlypublished.27

Linear b-amino acids

The b-alanine itself has been found able to generate differentnanostructures depending on the solvent, temperature, and surfacefunctionality of the materials on which it is assembled. As anexample, N,N-dicyclohexylurea-b-alanine adduct forms nanovesi-cles in methanolic solutions. These nanovesicles have been usedto encapsulate metotrexate, a potent anticancer drug, suggestingtheir potential use as a drug carrier.28

Fig. 21. Dipeptide nanotubes containing b2,3-diarylamino acid.

CO2H

NH2

CO2H

NH2

CO2H

NH2

ACBC ACPC ACHC ABHEC

CO2H

NH2

CO2H

NH2

ACHEC

Fig. 22. Examples of cyclic b-amino acids.

F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550 5547

b-Alanine homotetramers (H2N–bAla–bAla–bAla–bAla–CONH2)form nanovesicles in an aqueous medium. These vesicles are ableto encapsulate L-DOPA, and to release it by lowering the pH to6.2. The driving force in nanovesicles formation is a conformationalswitch in the helical structure of the peptides during the self-assembly. TEM and SEMmicrographs show that the self-assembledpeptides form spherical particles with diameters in the range of100 nm to 250 nm and possess a central core.29

A large number of papers deal with the self-assembly ofb3-amino acids, while, to the best of our knowledge, no examplesare reported on b2-amino acids. b3-Dipeptides containing b-pheny-lalanine are able to form different nanostructures depending onenvironment conditions (pH, temperature, solvent). With respectto a-Phe-Phe nanoarchitectures, b-phenylalanine dipeptides pos-sess thermal and proteolytic stability and can be used in biomedi-cal applications.30 They have also been used for decorating carbonnanotubes that self-assemble forming regular dendritic-like mor-phologies.31 Aguilar works show that ultrashort b3-peptides, con-taining different side chains, spontaneously self-assemble intofibers from solution in a unique head-to-tail fashion. It is possibleto obtain large structures that can be seen with the naked eye andhandled easily.32 Side chain polarity does not affect their ability toundergo head-to-tail self-assembly into helical nanorods. Theythus represent a robust self-assembling platform that can supportpolar functional groups in fibrous nanomaterials. As applications,helical N-acetylated b-tripeptides can form hydrogel that can bedecorated with cell adhesion signals IKVAV and RGD obtainingbioscaffolds that support the growth of cells.33 Helical bundlescomposed of b3- and a/b3-peptides have been extensively studiedby Gellman and by several other research groups (see also belowin cyclic paragraph). It has been demonstrated that the packingof b-314 helix into coiled-coils of varying stoichiometries is a func-tion of amino acid sequence. These helical bundles have been usedin several applications, such as metal ion binding,34 catalysis35 andcation nanochannels mimics.36

Few examples of nanostructures formed by linear disubstitutedb2,3-amino acids are reported. Dipeptides containing a fluorine sub-stituted b2,3-diarylamino acid and L-alanine (Fig. 21) self-assembleinto proteolytic stable nanotubes, that are able to load small mole-cules and enter the cells locating in the cytoplasmic region.37

11-Helical a,b2,3-hybrid peptides give access to hexagonal orrod-like microcrystalline structures depending on the chemicalenvironment and on the sequential use of organic solvents duringthe self assembly.38

Cyclic b-amino acids

b2,3-Cyclic b-amino acids have been widely used for the prepa-ration of both b- and a, b-peptides. As observed for linear aminoacids, they are able to induce the formation of molecular architec-tures that self-assemble in different geometries.

Ortuño and co-workers deeply studied systems containingcyclobutane b-aminoacids (ACBC, Fig. 22), and investigated theeffect of cis/trans stereochemistry on molecular organization. Smallanionic amphiphiles, containing a lipophilic chain anchored to theamino function of ACBC, form spherical micelles, with a morphol-ogy depending on the stereochemistry. In diluted solutions, the cisgeometry stabilizes the headgroup solvation and the anionic-charge, through intramolecular hydrogen-bonding and charge-dipole interactions. Furthermore, the relative configuration ofACBC influences the chiral recognition ability of the sphericalmicelles for bilirubin enantiomers.39 b-Dipeptides containing twotrans-ACBC, or one trans and one cis fragment, assemble intonanoscale helical aggregates that form solid-like networks. Thegel–sol transition temperature of this gelator is around 270 K intoluene at a concentration of about 15 mM.40 cis-ACBC dipeptidesfunctionalized with the p-electron-rich tetrathiafulvalene (TTF)moiety form fibers able to conduct electricity.41 By increasing thenumber of cis-ACBC, the formation of six-membered hydrogen-bonded rings is induced and a strand conformation is observed insolution. These oligomers self-assemble into nano-sized fibers.42

Seung-Lee and co-workers devised the new term ‘‘foldectures”,indicating any 3D molecular architecture that is derived from theself-association of foldamers in solution. They showed that helicalb-peptide foldamers self-assemble into 3D molecular architecturewhen they are composed of trans-(R,R)-2-aminocyclopentanecar-boxylic acid (trans (R,R)-ACPC, Fig. 22) and C-protected with a ben-zyl group. In particular, they observed that four individual left-handed helical monomers constitute a right-handed superhelixsimilar to the supercoiled structure of collagen.43 The 7-mersequence, that in organic solution possesses a 12-helical structure,self-assembles into a homogeneous windmill-shaped morphologyin an aqueous environment.44 The hexamer gives rise to nanoarchi-tectures with a molar tooth shape in aqueous solution.43 Startingfrom the shorter trans-ACPC tetramer, microtubes with a rectangu-lar cross-section can be observed. What is relevant is that the tet-ramer lacks full helical propensity in solution. The self-assembly isindeed solvent evaporation induced.45 Recently, the authors dis-covered that these foldectures, as free carboxylic acids, uniformly

5548 F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550

align with respect to an applied static magnetic field, and possessinstantaneous orientational motion in a dynamic magnetic field(Fig. 23). These motions resemble the magnetotactic behavior ofmagnetosomes in magnetotactic bacteria.46

The self-assembly of a/b-peptide foldamers containing ACPCand Aib was also studied. These foldectures possess a 11 helixstructure in solution and give rise to parallelogram plate shapesin the solid state47 and to hollow truncated trigonal bipyramidshapes in water.48

b-Peptides containing trans-2-aminocyclohexanecarboxylicacid (trans-ACHC, Fig. 22) in solution form H14 helices thatself-assemble into helix bundles, vesicle-forming membranes,

Fig. 23. Alignment of trans-ACPC foldectures by static magnetic field. (a) Schematicdiagram of experimental process for alignment of foldectures under static magneticfield. (b) SEM images of rhombic rod foldectures (F1) deposited on Si substratesunder (left) in-plane magnetic field and (right) out-of-plane magnetic field. (c) SEMimages of rectangular plate foldectures (F2) deposited on Si substrates under (left)in-plane magnetic field and (right) out-of-plane magnetic field. Arrows and circlesindicate direction of magnetic field. Scale bars, 5 lm. (From Kwon S, et al. NatCommun, 2015, doi: http://dx.doi.org/10.1038/ncomms9747).

O

OO

HN

MeO2C

OMeO2C

HN N

NHO O

sugar β-AA AZT β-AA

R

O O

R16

R =

Bolamphiphiles

Fig. 24. Bolamphiphiles containing cyclic b-amino acids.

and lyotropic liquid crystals.49 On the other hand, cis-ACHC pep-tides possess H10/12 helix conformation that in water self-assemblewith the formation of vescicles with an average diameter of100 nm. A similar behavior is observed for b-peptides containingcis-ACHEC (Fig. 22) and exo-ABHEC (Fig. 22).50 Dipeptides contain-ing cis-ACHC together with either Aib or L-Phe form organogelthrough the self- assembly of monomers possessing turn-typeb-sheet arrangement. This gel has been used for oil spill recoveryfrom a biphasic mixture of oil and water.51 Synthetic polymerscontaining ACHC and cationic b2,3 substituted amino acid havebeen developed by Gellman. These nylon-3 polymers (poly-b-pep-tides) display significant and selective toxicity toward the mostcommon fungal pathogen among humans, Candida albicans.52

Cyclic b-amino acids containing the furanosyl ring (Fig. 24) havebeen used for the synthesis of bolamphiphiles, molecules havingtwo hydrophilic groups at both ends of a sufficiently longhydrophobic hydrocarbon chain. These compounds self-assemblein different structures depending on the hydrophilicity/hydropho-bicity of the heads.53

c-Amino acids

Recently, c-amino acids have gained increasing attention con-sidering them as molecular building blocks for nanomaterials.Although the introduction of two additional carbon atoms on thebackbone reduces the number of potential hydrogen bonds, c-pep-tides adopt various stable conformations, such as helices, sheetsand turn.54 In particular, c-peptides helices are surprisingly stableand have been observed for ultra-short sequences. The conforma-tion stability is increased by introducing substituents on the back-bone chain (c4–, c4,2–, c4,4-amino acids, Fig. 25).

Oligomers containing c-cyclobutane amino acid and 4-aminoProline (Fig. 25) have been studied by Ortuno et al.55 These pep-tides have high tendency to aggregation providing stable vesiclesof nanometric size.

Helical peptides containing m-aminobenzoic acid (MABA,Fig. 25) form a supramolecular sheet structure in polar protic sol-vent, caused by a conformational switch of the helical strand to amore open (extended) structure. However, in solvent like chloro-form the helical structure helps to accommodate the second mole-cule in the intertwining processes and thus increases the stabilityof the supramolecular double helix.56 Dipeptides containingMABAin combination with several a-amino acids, form pH-sensitivenanostructures through aromatic p–p interactions. At acidic pH(pH 4.2–6.0) nanowires have been observed, while increasing thepH of the solution, only nanovesicles have been formed.57 As faras c-peptides composed of gem-dimethyl c4,4-amino acids(Fig. 25) are concerned, they adopt extended polar sheet typestructure and spontaneously self-assemble into nanofibrillarsuperstructures. Interestingly they display unprecedented ther-moreversible gelation in various solvents.58 In addition to thehomo-oligomers, the mixed sequences consisting of a- andhomologated b- and c-amino acids have been studied. The reasonbeing the variety of structures that can be generated by changingthe order and position of amino acids. Gopi and coworkers studiedthe self-assembling properties of a, c-hybrid peptides composed ofalternating a- and c-amino acids.59 All a,c 4-hybrid peptides show12-helical conformations in single crystals. Based on the nature ofthe c-amino acid side chains, they displayed remarkable divergentsupramolecular assemblies such as ribbons, fibers, rods and tubes.The heptapeptides with alternating a- and c-Phe residues showedremarkable elongated nanotubes which were explored as a tem-plate for biomineralization of silver ions to silver nanowires. Otherhybrid peptides, in particular c,a-hybrid peptides were studied byDas et al.60 Gabapentin (Gpn, Fig. 25) containing hybrid peptides

N

O HN

R ON

ONH

RO

nn

NH

NHHN

O

O

O

O

OH

OHHO

(a) (b)

F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550 5549

with sequence Boc-Gpn-Aib-Xaa-Aib-OMe (where Xaa = pheny-lalanine, leucine or tyrosine) show a C12/C10 hydrogen-bondeddouble turn conformation. The circular dichroism studies showdistinct CD patterns for the peptides in an aqueous methanol med-ium which can be attributed to the third residue side-chain effect.Both scanning and transmission electron microscopy observationsdemonstrate solvent dependent self-assembled morphologicalfeatures.

ON

O

NHR

n

m OHHO OHO

Fig. 26. a) and b) Cyclic peptides containing c-Ach.

O NH

NHOHN

HNO

O

O

OO

O

O

O

O

OO

O

Fig. 27. Cyclic peptides containing (S)-b-Caa and R-Ama.

NNN

O

O

O NH O

OO NN N

O

OO

O O

O

O

O

O

NH

OHN

NH

NNNO

O

NHO

HNO

OHN

O N NN O

HN

O

OO

O

O

O O

O

O

A B

Fig. 28. Cyclic peptides containing isosteric triazole amide replacement.

Cyclopeptides

Several classes of cyclic oligopeptides self-assemble into pep-tide nanotubes (SPNs). SNPs are widely studied for their potentialapplications both in biology and materials science. By varying thenumber of amino acids in each ring, it is possible to control thediameter of the nanotube. On the other hand, the properties ofnanotube outer surface can be easily modified by varying theamino acids side chain. In particular, it is crucial that the cyclopep-tide adopts a flat conformation in which not only the amino acidsside chains of the peptide rings have a pseudo-equatorial outward-pointing orientation but also the carbonyl and amino groups of thepeptide bonds are oriented perpendicular to the ring.61

Cyclic homo-c-tetrapeptides based on cis-3-aminocyclohex-anecarboxylic acid (c-Ach, Figs. 25 and 26) residues, self-assembleto nanotubes.62 Cyclic octapeptides composed of a-amino acidsalternated with cis-c-Ach (Fig. 26a), self-assemble as drumlikedimers through b-sheet-like, backbone-to backbone hydrogenbonding.63

Several other recent examples of cyclic peptides incorporatingsugar-like scaffolds have been reported. Granja and coworkersreported on peptide nanotubes composed exclusively of cyclic c-amino acids with a saccharide-like outer surface.64 Amphiphiliccyclic peptide composed of two b-glucosamino acids and onetrans-2-aminocyclohexylcarboxylic acid (Fig. 26b) self-assembledinto rodlike crystals or nanofibers depending on preparativeconditions.65

The synthesis and the structural investigation on a cyclictetrapeptide containing alternating a C-linked sugar b-amino acid((S)-b-Caa) and R-aminoxy acid 2 (R-Ama) was reported by Sharma(Fig. 27).66 At higher concentration this cyclic peptide formsnanorod aggregates as evidenced from TEM and AFM analysis.

Replacement of amide bond by triazole isoster leads to cycleswith very interesting properties which have been deeply studiedby Chattopadhyay and coworkers.67 For instance, two types ofnovel heterocyclic backbone modified macrocyclic peptides havebeen obtained by incorporating an a- or b–amino acid and cis-b–furanoid (1,4)-linked triazole amino acid (Fig. 28). The macro-cyclic peptide A, featuring a-amino acid, is able to maintain pseudocyclopeptide conformation with predictable self-assembly pattern,while B, based on b-amino acid, forms only a conformationallyhomogeneous cyclic peptide that does not undergo self-assembly.

CO2HH2N

HH2N

R

CO2H

MABA

γ4-amino acid

NCO2H

H2N

R4-amino-Pro

H2N COOH

γ-Ach

Fig. 25. Examples of

Conclusions

Many synthetic efforts are devoted to obtaining new and differ-ent non-standard amino acids, claiming their importance in thedevelopment of new smart nanomaterials. In principle, the func-tional variability on the amino acid scaffold could be endlesslyintroduced, leading to an infinite number of molecular combina-tions and architectures. While a huge number of synthetic method-ologies have been developed, the application of non-standard

2N

CO2HH2N

CO2H

Gpn

γ4,4-amino acid

CO2HH2N

γ4,4-cyclobutane-amino acid

c-amino acids.

5550 F. Clerici et al. / Tetrahedron Letters 57 (2016) 5540–5550

amino acids in nanomaterials preparation has yet to be completelyexploited.

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