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Peptidomimetics via modifications of amino acids and peptide bonds† Ilker Avan,a C. Dennis Hallb and Alan R. Katritzky‡*b Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptides used in therapy. Self-structural organizations such as turns, helices, sheets and loops can be accessed by chemical modifications of amino acids or peptides.

Received 28th October 2013

In-depth structural and conformational analysis and structure–activity relationships (SAR) offer a way to

DOI: 10.1039/c3cs60384a

establish peptidomimetic libraries. Herein, we review recent developments in peptidomimetics that are formed via heteroatom replacement within the native amino acid backbone. Each sub-section describes

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structural features, utility and preparative methods.

1. Introduction Peptides and proteins play vital roles in almost all biological and physiological processes. Since they function as hormones, enzyme inhibitors or substrates, growth promoters or inhibitors and neurotransmitters, life without them would be impossible.1–4 The therapeutic application of peptides and proteins is of a

Department of Chemistry, Faculty of Science, Anadolu University, 26470, Eskis- ehir, Turkey b Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, USA. E-mail: [email protected]; Fax: +1 352-392-9199; Tel: +1-352-392-0554 † Dedicated to the memory of Alan Roy Katritzky a great scientist and mentor. ‡ Deceased February 10th, 2014.

Ilker Avan was born in Eskis- ehir, Turkey, in 1980. He received his BS and MS degrees from Anadolu University, Turkey. In 2008, he joined the research group of Prof. Alan R. Katritzky at University of Florida as a research scholar and he obtained a second MS degree from the University of Florida in 2011. He completed his PhD degree at Anadolu University in 2012 under the supervision of Ilker Avan ¨ven and Prof. Prof. Alaattin Gu Alan R. Katritzky. He is currently working at Anadolu University as a postdoctoral research and teaching assistant. His research focuses on the design and the synthesis of heterocyclic drug candidates and synthesis of peptidomimetic compounds.

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burgeoning interest to diverse areas such as neurology, endocrinology and hematology. The use of peptides as drugs, however, is complicated by their bioavailability and biostability.1–4 Rapid degradation by proteases, poor oral availability, difficult transportation through cell membranes, nonselective receptor binding and challenging, multistep preparation are the major limitations of peptides as active pharmaceutical ingredients.4 Hence, small, protein-like chains called peptidomimetics have been designed to mimic native analogs and conceivably exhibit better pharmacological properties.5–7 Peptidomimetics have been prepared by cyclization of linear peptides8–10 and/or coupling of stable unnatural amino acids.5–7,11 Unnatural amino acids can be generated from their native analogs via modifications such as amine alkylation,12–16 side

C. Dennis Hall

C. Dennis Hall, after retiring from his academic position at King’s College, London, in 1999, joined Alan Katritzky’s research group at the University of Florida where he acts as a group leader, the administrator of the on-line journal ARKIVOC and a co-organizer of the Florida Heterocyclic/Synthesis conferences (Flohet). After joining the Katritzky team he has co-authored some 50 papers in the fields of heterocyclic chemistry, QSAR, insect control and synthetic ion channels.

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Fig. 1

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Peptidomimetic manipulations of native amino acids.

chain substitution,17–19 structural bond extension,20–23 cyclization,24,25 and isosteric replacements7,26 within the amino acid backbone. Isosteric replacements within a peptide backbone constitute an important aspect of peptide chemistry because of the effects on the resultant peptidomimetic. Such replacements confer diverse electrostatic properties and new secondary conformations on the peptidomimetic chain, often resulting in improved pharmaco-kinetic properties. This review focuses on the synthesis and properties of peptidomimetics formed by isosteric atom replacement in the amino acid backbone.

Alan R. Katritzky was educated at Oxford and Cambridge (lecturer and Founder Fellow of Churchill College). Founder Dean of the School of Chemical Sciences at East Anglia since 1962, he transferred in 1980 as inaugural Kenan Professor to the University of Florida. His research on heterocyclic chemistry covered inter alia N-oxides, benzotriazole methodology, electrophilic and nucleophilic substitution, computational QSPR Alan R. Katritzky relationships, and peptide chemistry. He holds 14 honorary doctorates from 10 Eurasian countries and associate or foreign membership of five national academies. He is Cavalieri Ufficiale (Italy) and Honorary Fellow of St. Catherine’s College, Oxford, and of the Polish and Italian Chemical Societies. Over 1000 graduate students and postdocs have been trained in his group. He created the not-for-profit Arkat USA Inc., is the organizer of the Flohet Conferences, and the publisher of the open access journal ARKIVOC, which is completely free to authors and readers.

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Backbone modifications of amino acids can be categorized as follows: (i) changing the amino functionality; (ii) replacement of a-CH; (iii) extension of the backbone by one or two atoms and (iv) atom modification of the carbonyl function (Fig. 1). Although of potential therapeutic value, carbonyl group replacement will not be considered within this review.

2. Isosteric replacement of the amino functionality An important subset of peptide mimicry is the replacement of the amino functionality by an isosteric atom (Fig. 2). This modification has a significant effect on the secondary structure of peptides and their folding properties by changing the H-bonding pattern. 2.1

Depsipeptides

Isosteric replacement of at least one amino group in the peptide chain by an oxygen atom leads to the formation of depsipeptides. Elimination of the N–H group results in a decrease of H-bonding capability, responsible for secondary structure and folding patterns of peptides, thus inducing structural distortion in helix27–29 and b-sheet26,30,31 structures. Due to decreased resonance delocalization in esters relative to amides, depsipeptides have lower rotational barriers for cis–trans isomerization than their native analogs and therefore have more flexible structures.32,33 Natural depsipeptides, especially cyclic species, have been isolated from many micro-organisms such as fungi, bacteria,

Fig. 2

Isosteric atom replacement of the amino functionality.

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Fig. 3

Didemnin B, romidepsin (FK228), valinomycin and nonactin.

and marine organisms and they exhibit a wide spectrum of biological activity including antimicrobial, antifungal, antiinflammatory, antitumor, and immunosuppressive activity. Other important therapeutic properties of natural depsipeptides are related to anticancer and anti-HIV activity.34,35 A cyclic depsipeptide, romidepsin (FR228) (Fig. 3) originally extracted from the bacterium Chromobacterium violaceum, is an FDA-approved anticancer drug under the trade name Istodaxt used for the treatment of cutaneous T-cell lymphoma.36–38 Extensive phase II studies of dolastine-10 and didemnin B revealed their anti-tumor activity.39–41 Callipeltins and papuamide A show promising inhibitory activity against HIV.42,43 The cyclic depsipeptide, valinomycin (Fig. 3) is a potassium selective ionophore44 and nonactin (Fig. 3) is a symmetric polyester and natural ionophore, selective for ammonium ions.45

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Synthetic polymers and copolymers of depsipeptides are important in biomedical science with potential use as biomaterials for controlled drug release systems and biodegradable scaffolds in tissue engineering.46 These polymers are easily biodegradable materials that support cell growth and disappear as tissue regenerates after surgery.47 Various polydepsipeptides are prepared by ring-opening polymerization of morpholine-2,5-dione derivatives.48 Since the discovery of the depsipeptide family, many synthetic approaches have been reported for the formation of the ester bond. Methods for the preparation of depsipeptides require the activation of a carboxylic acid site and subsequent reaction with a-hydroxy acids to give depsipeptides. Many coupling reagents, alone or in combination, such as CDI,49 DIC/DMAP,50 DCC/ DMAP,51,52 EDCI/DMAP,53 PyBroP/DIEA54 have been employed to form unstable intermediates in situ. Moreover, asymmetric mixed anhydrides were produced using benzenesulfonyl chloride with pyridine or under Yamaguchi conditions (TCBC, DIEA, DMAP)55 for coupling with a-hydroxy acids (Scheme 1). A study by Davies et al.56 revealed that CDI, DCC/DMAP and mixed anhydride couplings gave yields near 50% but couplings via TBTU, TNTU and TSTU gave lower yields (6–33%). The best yields were achieved using acid chlorides (61%), urethane-Ncarboxyanhydrides (80%) and by PyBroP coupling (82%). Another study of coupling reagents by Kuisle et al.50 showed variable yields (2–92%) and coupling times of 2–20 h with the best results (92%, 2 h) being obtained using DIC in the presence of DMAP. Recently, in our group, O-Pg(a-hydroxyacyl)benzotriazo-les 6 and N-Pg(a-aminoacyl)benzotriazoles 7 were prepared as stable intermediates and coupled with unprotected a-hydroxyl acids 8 and amino acids to construct depsipeptides 10 via O-acylation (47–76%), N-acylation (74–94%) and chiral oligoesters 9 (75–86%) (Scheme 2).57,58 Synthesis of depsipeptides has also been accomplished on solid phase. Fragments which already

Scheme 1

Construction of the depsipeptide link under Yamaguchi conditions.

Scheme 2

Benzotriazole-mediated preparations of chiral oligoesters 9 and depsipeptides 10 via O-acylation of unprotected a-hydroxyl acids 8.

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have an ester bond can be coupled via N-acylation on solid phase to construct longer analogs.49 Coupling of amino acids and a-hydroxy acids is another methodology which enables both O and N acylation on solid phase. The first solid phase synthesis of a linear tetra-depsipeptide containing three a-hydroxy acids was accomplished via mixed anhydride methodology in which the ester bond was formed in pyridine by benzenesulfonyl chloride activation.59 Recently, two protocols have been used in the solid phase synthesis of depsipeptides. Davies et al. used a protocol in which HATU and PyBroP coupling of a-hydroxy acids was achieved on Wang resin. t-Butyldimethylsilyl groups were used for hydroxy protection, and were then deprotected by t-butyl ammonium fluoride.54 Another protocol, devised by Kuisle et al.,50 includes ester bond formation by DIC/DMAP coupling of a-hydroxy acids. The tetrahydropyranyl (THP) group was preferred for hydroxyl protection and deprotection was achieved by treatment with p-TSA. The esterification process with DIC/DMAP was monitored by a color test with 4-(p-nitrobenzyl)pyridine and the linear depsipeptides were cleaved from Wang resin by TFA/CH2Cl2.60 Cyclization of linear depsipeptides via esterification was accomplished under Mitsunobu conditions50,61 and via amidation using acid chlorides or by HATU coupling.50 2.2

Thiodepsipeptides

The replacement of the amide nitrogen of a peptide bond by a sulfur atom generates a new class of peptides known as thiodepsipeptides. The thioester bond of natural thiodepsipeptides results from thioesterification of a cysteine thiol group by the carboxylic group of amino acids, N-alkylamino acids or hydroxy acids. Macrocyclic thiodepsipeptides have been isolated from natural sources and have found valuable applications in medicine.62–66 Thiocoraline (Fig. 4) is a potent

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macrocyclic antitumor antibiotic isolated from Micromonospora sp. and Verrucosispora sp.62,63,67 Boger et al. first synthesized thiocoraline and established the relative and absolute stereochemistry of the two pendant 3-hydroxyquinoline chromophores.68 The key thiol esterification reaction between tripeptide 11 and protected D-cysteine derivative 12 in Boger’s thiocoraline synthesis was accomplished under near racemization-free conditions by the use of EDCI-HOAt to afford the thiodepsipeptide 13 (83%, de 95 : 5) (Scheme 3).68 In the same study, Boger et al. reported that thiocoraline and its analog, BE-22179, have high binding affinity for DNA and show notable cytotoxic activity against the L1210 cell line at pico-molar levels.68 Nosiheptide (Fig. 4) is another macrocyclic thiopeptide antibiotic, originally isolated from Streptomyces actuous 40037.69 Although the synthesis of nosiheptide has not yet been completed, Kimber and Moody achieved the synthesis of the southern hemisphere of nosiheptide by a macrocyclic thioesterification reaction using DCC or PyBOP.69 Acyclic thiodepsipeptides have also been subjected to many microbial assays. Oligothiopeptides (Fig. 5) composed of a-thiocarboxylic acids and native amino acids were used as thioester substrates to evaluate the enzymatic activity of Streptomyces R6170,71 and Actinomadura R3972 DD-peptidase. Appleton et al. prepared the thia-analogues of 5-aminolaevulinic acid (ALA) which were examined as potential inhibitors of ALA dehydratase.73 Cao et al. showed that fatty acid glycolates and their thioesters have inhibitory effects against small cell lung carcinoma peptidylglycine a-amidating monooxygenase (PAM).74 The thioester linkage in the above thiodepsipeptides was established by the use of DCC or CDI coupling reagents. Ura et al. recently developed a new procedure using ring-opening polymerization of 1,4-thiazine2,5-diones for the preparation of polythioesters composed of alternating chiral a-amino acids and a-thiocarboxylic acids.75

Fig. 4 Thiocoraline and nosiheptide.

Scheme 3

Thiol esterification reaction between tripeptide 11 and the D-cysteine derivative 12.

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Fig. 7 Nucleobase attachment onto cysteine-peptide via transthioesterification.

Fig. 5

Acyclic thiodepsipeptides examined for their enzymatic activities.

Moreover, peptide thioesters, especially cysteine thioesters, have found great synthetic utility in native chemical ligation (NCL), a powerful chemical tool to obtain longer peptides and proteins. NCL links a peptide C-terminal activated thioester and an N-terminal cysteine-containing component to form a single amide ligation product (Fig. 6).76,77 NCL starts by a transthioesterification process between an active thioester (pepA) and free thiol of the N-terminal cysteine residue (pepB) to generate an S-acyl peptidic intermediate and ends by an S-to-N acyl transfer to form a new native amide bond. Recent conceptual progress in the field of S- and O-acyl ligation in isopeptides has been reviewed by Monbaliu and Katritzky.77 Gellman and co-workers created a new methodology, called ‘‘Backbone Thioester Exchange’’ (BTE) to explore the conformational-structural stability and preferences of peptides.78–84 In BTE methodology, a native amide bond in a polypeptide is replaced by a thioester linkage to generate a new peptide containing a thioester bond (thiodepsipeptide) which then undergoes a thiol–thioester exchange reaction with another thiol-containing peptide in aqueous solution at neutral pH.78 The equilibrium constant of thiol–thioester exchange provides complementary information about conformational, folding and packing features of the original peptide.78–84 In recent work by Ghadiri and coworkers, nucleobases were introduced into cysteine-containing peptides via reversible thiol–thioester exchange reactions (Fig. 7) to afford thioester peptide nucleic acid (tPNA) scaffolds which undergo dynamic sequence modifications (nucleobase exchanges) resulting from the addition of complementary DNA or RNA templates.85 In a

Fig. 6

similar approach, transthioesterification methods were used (a) to generate dynamic cyclic thiodepsipeptide libraries86 and (b) in the development of nanobiosensors for detection of a specific chemical at very low concentrations.87

3. Replacement of a-carbon Many new pseudo peptides and peptidomimetics have been generated as a result of modifications of the a-carbon of peptides, including inversion of configuration at an a-carbon, replacement of the a-hydrogen (by the alkyl or other group), and isoelectronic replacement of the a-carbon atom by a heteroatom (mostly nitrogen). These common operations on the a-carbon of peptides result in novel peptidic compounds with different secondary structures and new pharmacological properties. 3.1

Azapeptides

Replacing the a-carbon of an amino acid of a peptide with nitrogen generates a new class of compounds called ‘‘azapeptides’’, (Fig. 8) in which the replacement of the rotatable Ca–C(O) bond by a rigid urea Na–C(O) causes significant changes in both chemical and biological properties of the parent peptide.88,89 This replacement eliminates chirality at the a-position and decreases the electrophilicity of the carbonyl group by altering the geometry of the a position from tetrahedral to trigonal (i.e., planar, achiral), with dihedral angles (j = 901  301 or 901  301, and C = 01  301 or 1801  301) providing b-turn conformations.90–93 b-Turn azapeptide conformations have been demonstrated by X-ray crystallography,94–96 spectroscopy,97,98 and by computational models90,92,93 (Fig. 9). Since azapeptides are more resistant to enzymatic hydrolysis, they are attractive targets for drug design. For example, azapeptides

Native chemical ligation.

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Fig. 8 Aza-peptide and azatide.

Fig. 9 H-bonding pattern and b-turn of the X-ray crystal structure of BocPhe-azaPhe-Ala-OMe (X-ray data reproduced from ref. 94, Tetrahedron Lett., 2009, 50, 4158. Copyright (2009), with permission from Elsevier.).

have been used as inhibitors of serine and cysteine protease,99,100 human neutrophil protease 3,101 hepatitis A virus (HAV) 3C protease,102 hepatitis C virus NS3 serine protease103 and HIVprotease.104,105 Atazanavir (Reyatazt), an FDA-approved antiretroviral drug is a highly active azapeptide inhibitor of the HIV protease.105–107 Systematic replacement of amino acid residues in native peptides with their aza counterparts is called ‘‘aza-amino acid scan’’. Nowadays it is very common to investigate structure-activity relationships (SARs) of aza-peptides as well as to generate novel peptidic drug candidates with improved pharmacological and pharmacokinetic properties. Biologically active peptides including hormone analogues, e.g. luliberin (luteinizing hormonereleasing hormone)108 and enzyme inhibitors such as peptidebased protein kinase B (PKB/Akt) inhibitors, PTR6154,109 were subjected to aza-amino acid scan studies. Moreover, aza-analogs of antagonist and agonist peptides, including human calcitonin gene-related peptide (hCGRP) antagonists,88,91 cyclic integrin receptor antagonists,110 potent melanocortin receptors agonist,111

Scheme 4

Synthesis of Na-substituted ethyl carbazates 20.

Scheme 5

Azapeptide construction.

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and growth hormone releasing peptide-6 (GHRP-6)98,112–114 have been prepared in order to explore their biological activity and secondary structure. In fact azapeptides are semicarbazide analogs of natural peptides where the Ca has been replaced by NH, generating the –NHNHC(QO)NH– structure. Therefore, aza-peptides are constructed from substituted hydrazines or hydrazides by formal coupling with carbonyl-donating reagents followed by amino acid coupling or by direct coupling with isocyanates. Early examples of azapeptides were reported by Ronco et al. who synthesized azapeptides from ethyl carbazate.115,116 This method includes three steps: (i) aldehyde protection of the – NH2 terminus of carbazate 17, (ii) alkyl substitution of adjacent nitrogen and (iii) elimination of aldehyde to afford Na-substituted ethyl carbazates 20 as free aza-amino carboxylates (Scheme 4).115 The following stages of azapeptide preparation constitute the basis of current aza-amino acid preparation in both liquid and solid phases.117,118 Boc-hydrazide 21 was first treated with the appropriate aldehyde 22 to give hydrazones 23, then hydrogenated over Pd/C to yield N-Boc-N 0 -alkylhydrazines 24. Subsequently, there are two possibilities to form azapeptidic structures. The first is by treatment of N-Boc-N 0 -alkylhydrazine with isocyanates 25 derived from amino acids via carbonyl donating reagents. The second is to treat N-Boc-N 0 -alkylhydrazines directly with carbonyl donating reagents 26 to produce stable or unstable intermediates 27 followed by coupling with nucleophilic species including amino acid esters 28 (or resin bounded amine derivatives) to obtain aza-peptides 29 (Scheme 5).119,120 Intramolecular hydantoin formation during aza coupling is a serious drawback resulting in low reaction rates and tedious purification procedures.88 Carbonyldiimidazole,121,122 bis(pentafluorophenyl)carbonate,118,123,124 p-nitrophenylchloro-formate,98,112 bis(2,4-nitrophenyl)carbonate,89 triphosgen125 and phosgene88,126,127 in toluene solution have all been used as carbonyl donating reagents.

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Fig. 10 Preparation of Na-substituted azapeptides via regioselective alkylation of peptide-bound aza-Gly (adapted with permission from ref. 112, J. Am. Chem. Soc., 2011, 133, 12493. Copyright (2011) American Chemical Society.).

Boc, Fmoc, Cbz and Ddz groups for hydrazine protection are often applied in both solid and liquid phase syntheses of azapeptides.88,109,122,127 In an aza-scan study, aza analogs of PKB/Akt inhibitors were synthesized from aza-arginine and aza-proline precursors by microwave-assisted SPPS.109 Regioselective alkylation of peptide-bound aza-Gly residues was recently reported as a versatile preparative method for the Na-substituted azapeptides on a solid support.98,112,113,128 This process consists of (a) acylation of the solid supported peptide with a hydrazoneprotected activated carbazate, (b) regioselective alkylation of semicarbazone, and (c) deprotection of semi-carbazone (Fig. 10). Subsequently Fmoc-based SPPS, sequential amino acid couplings, removal of Fmoc protection and cleavage from the solid support yield Na-substituted azapeptides.98,112,113,128 3.2

Azatides

Azatides or ‘‘pure azapeptides, suggested by Janda, are peptidomimetic biopolymers in which a-aza-amino acids are linked in a repetitive manner.124 A wide variety of Boc-protected a-azaamino acids were prepared as monomers and coupled to provide azatides (leu-enkephalin mimetics) in a linear, stepwise, chainlengthening fashion by solution- or liquid-phase synthetic methods.124,129 Bis(pentafluorophenyl)carbonate was used as a carbonyl activating reagent in the coupling reactions. 3.3

Azadepsipeptides

Azadepsipeptides are hybrid types of peptidomimetic compounds formed by linking azapeptides with depsipeptides. Azapeptides lack chirality due to Ca replacement by N, and depsipeptides suffer from loss of the H-bonding character of NH. Thus, the azadepsipeptides show characteristic features of parental pseudo peptides. Dyker et al. described the first

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Fig. 11 PF1022A 30 and bis-aza PF1022A 31.

synthesis of azadepsipeptide precursors 36, which were subsequently used in the preparation of a bis-aza analogue of the antiparasitic cyclo-octadepsipeptide PF1022A 31 (Fig. 11).130 In the same study, two different routes were followed to obtain the dimeric azadepsipeptide precursors. In the first, N-Boc protected N,N 0 -dialkyl hydrazines 35 were coupled with in situ-generated 34 derived from a-hydroxy carboxylic esters 32 (Scheme 6). In the second, carbazate derivatives 38 were formed by reaction of hydrazines 35 with carbon dioxide and a-bromo acetate 37 (Scheme 7).130 The second route was limited to the use of primary alkyl halides since secondary halides underwent elimination to give a,b-unsaturated esters under basic conditions.130 This limitation was recently overcome by using a quaternary ammonium salt base (Triton-B)131 or a basic resin.132 The azadepsipeptidic building blocks and the remainder of the natural components were linked together by a BOP-Cl coupling reagent to assemble the bis-aza analogue of cyclooctadepsipeptide PF1022A. The structural analysis of bis-aza PF1022A 31 by X-ray and NMR showed no significant differences from natural PF1022A 30, but, these bis-aza analogs PF1022A 31

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Scheme 6

Preparation of azadepsipeptides through activated formats.

Scheme 7

Preparation of azadepsipeptides by forming carbamic acids generated in situ.

exhibited a lower anthelmintic activity relative to the natural analog (Fig. 11).130 In another study, by Cabaret et al., benzoxazinone-containing azadepsipeptides and linear homologs were prepared starting from ortho- and meta-hydroxybenzoic acids.133 These compounds, however, showed no inhibitory activity against b-lactamase or 133 DD-peptidase despite the activity of parental depsipeptides. This is analogous to Dyker’s activity study, in which aza modification of depsipeptides resulted in a decrease or loss of biological activity of the parental depsipeptide.130

4. Backbone extension Insertion of extra carbon or other atoms between the carboxyl and the amino groups of an amino acid is a useful synthetic strategy to achieve novel peptidic oligomers in a large number of constitutional and configurational isomers.22,134–142 Pioneering research, notably by Seebach and Gellman, revealed that backboneextended peptides derived mostly from b or g-amino acids and their cyclic analogs can adopt ‘‘protein-like’’ secondary structures, such as helices, sheets and turns.134–139,142–145 Unusual intramolecular hydrogen-bonds and substitution patterns on the oligomeric backbone determine the secondary and tertiary structures of peptidomimetics in various solvents.142 The outstanding stability toward proteolytic enzymes139,142 and extended pharmacokinetic properties of backbone extended peptides137,146 encouraged interest in their therapeutic potential.137,139,147 Replacement of a carbon atom in backbone-extended amino acids with an atom such as oxygen or nitrogen opened up a new era in the exploration of peptidomimetic scaffolds, namely aminoxy and hydrazino acids (Fig. 12).11,148 Aminoxyacids are oxo analogs of backbone-extended amino acids bearing an extra oxygen atom instead of carbon next to nitrogen; hydrazino acids are their aza counterparts.11,148

Fig. 12

Heteroatom backbone extended peptidomimetics.

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The presence of an adjacent atom with lone pair electrons next to nitrogen ensures an alpha effect (influential on secondary structures) which increases the nucleophilicity of nitrogen, changes the torsional characteristics of bonds and affects H-bonding. To date, great efforts have been made to explore their folding properties and bioactivity.11,148–150 4.1

a-Aminoxypeptides

a-Aminoxy acids are in the b-amino acid family in which the b-carbon is replaced by an oxygen atom.148 Peptides composed of a-aminoxy acids have attracted special interest as novel foldamers,11,144,148 because of their unusual conformations and interesting bioactivity.150–156 Yang and co-workers have made extensive studies on the folding ability and potent biomedical uses of aminoxy peptides.148 a-Aminoxy acids have a higher propensity to form more rigid peptidic structures than natural analogs due to lone pair repulsion between heteroatoms which facilitates strong intramolecular hydrogen bonds between adjacent residues (Fig. 13).148,157–159 Homochiral a-aminoxy peptides show a strong tendency to form 1.88 helical structures through eight-membered-ring intramolecular hydrogen bonding (over a so-called ‘‘a N–O turn’’)148 which is independent of the side chain (Fig. 13–15).157,158,160–162 It has been shown that aminoxy peptides composed of L-aminoxy acids adopt a left-handed a N–O turn, while the peptides from 158–160,163 D-aminoxy acids adopt right-handed a N–O turns. Conformational studies revealed that heterochiral a-aminoxy peptides can form reverse turn structures, resulting in a loop conformation with two heterochiral N–O turns (Fig. 15).163 Hybrid peptides composed of consecutively-linked a-L-aminoxy and a-D-amino acids induced a 7/8-mixed helix generating a g-turn.164 Tetra- and hexa-hybrid peptides of a-aminoxy acids and carbo-b-amino provided robust 12/10-mixed helices.165

Fig. 13

D-a-Aminoxy

acid and an a-aminoxy oligomer with an a N–O turn.

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Fig. 14 H-bonding pattern in X-ray crystal structures of (a) monomeric and (b) dimeric a-aminoxy peptides (reproduced with permission from ref. 160, J. Org. Chem., 2010, 75, 4796. Copyright (2010) American Chemical Society).

Fig. 15 Reverse turn of a heterochiral a-aminoxy peptide in the X-ray crystal structure (reproduced with permission from ref. 163, J. Am. Chem. Soc., 2003, 125, 14452. Copyright (2003) American Chemical Society).

a-Aminoxy tripeptides consisting of an oxanipecotic acid dimer and a-aminoxy acid adopt rare folded structures with consecutive b- and g-turn like conformations in CHCl3.166 The folding properties of peptides derived from aminoxy acids were recently discussed by Li and Yang in a detailed review including results of theoretical and experimental studies.148 Cyclic and linear peptides of a-aminoxy acids have been reported to be good receptors for anions.11,167 Due to the higher acidity of aminoxy amide protons relative to amide protons,11 peptides containing a-aminoxy acids possess strong affinity for and good selectivity towards anions, especially chloride (Cl).168,169 For example, a compound derived from a-aminoxy acid forms a synthetic channel that can mediate passage of chloride ions across cell membranes.170 In another study, an a-aminoxy compound of C2-symmetry was utilized as an effective chemical shift reagent for measuring the ee value of carboxylic acids.170 Peptides containing a-aminoxy acids showed better hepatic, metabolic and gastrointestinal stabilities than natural peptides.156,171 Guanidinium-rich peptides of D and L a-aminoxy acids were investigated as Cell-Penetrating Peptides (CPP) and introduction of a-aminoxy acids into CPP backbones enhances their diffuse cytosolic distribution in living cells after direct membrane translocation.155 Furthermore, peptides consisting of a-aminoxy acids showed low toxicity and high resistance toward serum.155 The studies on aminoxy compounds provide a

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good indication that these compounds may find significant application in chemistry and therapeutic science. Peptides and hybrid analogs of a-aminoxy acids are usually constructed from their components by (i) using such peptide coupling combinations as BOP/HOBt/NEM, HBTU/HOBt/NEM, DIC/HOAt,172 EDCI/HOBt,159 TBTU/HOBt/DIEA,173 BOP/HOBt/ DIEA,166,174 iBuOCOCl/NMM,152 HATU, HCTU, HBTU, DIC/ HOBt,175 (ii) using an active ester of N-hydroxysuccinimide,176,177 and (iii) using N-protected(a-aminoxyacyl)benzotriazoles.178–180 The alpha effect of neighboring oxygen is not only manifest in the establishment of strong H-bonds in the aminoxy peptide backbone, but also increases the nucleophilicity of nitrogen. Therefore, it increases the overacylation of aminoxy NH in the coupling process. Overacylation may be prevented either by changing coupling reagents and conditions or by complete masking of nitrogen nucleophilicity.175 For example, reducing the basicity of a reaction mixture of HBTU and HATU circumvented the overacylation.175 Proper nitrogen protection may include (i) diprotection such as N,N,-di-Boc,176,177 (ii) difunctional groups like phthaloyl protection,148,159,172 or (iii) conversion into an oxime form (e.g. acetonoxime,181,182 and ethoxyethylidene oxime).176,177 The synthesis of aminoxy peptides starts with the preparation of aminoxy acids. The synthesis of aminoxy acids is mostly based on nucleophilic substitution of oxygen in N-hydroxycarbamates (urethanes),183–186 hydroxamic acids,186,187 N-hydroxy159,186 182 phthalimide or ketone oximes, followed by elimination of protecting groups to give free a-aminoxyacids. Although synthesis of a-aminoxy acids has been known for nearly a century, Testa et al. reported the first chiral preparation of aminoxy acids by reaction of chiral a-bromocarboxylic acid esters with ethyl hydroxycarbamate (N-hydroxyurethane) under basic conditions.184 Recently, Yang and co-workers used this methodology to synthesize D-N-Cbz-a-aminoxy acid esters from L-a-bromocarboxylic acid esters with inversion of configuration at a-carbon. Optical purities of N-Cbz-a-aminoxy esters that were formed after nucleophilic displacement of N-benzyloxycarbonyl-hydroxylamine (Cbz-NHOH) were checked by HPLC analysis and reported to be in the range of 92–94% ee.159 Due to the difficulties of Cbz-deprotection (further hydrogenation of free a-aminoxy acids gives amino acids), a new method containing a key step under Mitsunobu conditions was devised for the synthesis of chiral N-(Phth)-a-aminoxyacids.148,159 t-Butyl esters of D-N-(Phth)-a-aminoxyacids were prepared in 36–56% overall yield and in 95–99% ee starting from L-amino acids.159 The first solid phase synthesis of a-aminoxy oligomers was achieved by Shin et al. in a stepwise linking of D-N-phthaloyl protected a-aminoxyacids.172 Oligomers of aminoxy acids were grown on a PS-PEG resin by sequential coupling (BOP/HOBt/NEM for 6 h in DMF) and deprotection (5% hydrazine in MeOH for 15 min) steps until oligomers reached a defined length, when they were cleaved by the treatment with TFA–TES (98 : 2) for 1.5 h.172 4.2

b- and c-aminoxypeptides

Beta- and g-aminoxypeptides are chain-lengthened analogues of a-aminoxy acids. Compared to a-aminoxy acids, addition of an extra carbon atom to the aminoxy backbone allows more

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Fig. 16 b-aminoxy acid and b N–O turn of a b-aminoxy acid amide in the X-ray crystal structure (reproduced with permission from ref. 188, J. Am. Chem. Soc., 2002, 124, 9966. Copyright (2002) American Chemical Society and ref. 153, J. Am. Chem. Soc., 2004, 126, 6956. Copyright (2004) American Chemical Society, respectively).

substituent diversity and enables the formation of new subgroups of b- and g-aminoxypeptides. b-Aminoxy acids, analogs of g-amino acids, have one extra carbon atom compared to a-aminoxy acids (Fig. 16). Due to the variety of backbone extension and substitution in b-aminoxy acids, they form more flexible structures than a-aminoxy acids. Depending on substitution at Ca and Cb, b-aminoxy acids can be classified b2, b2,2, b3, b3,3 and b2,3. Yang and coworkers endeavored to elucidate the secondary structures of b-aminoxy peptides.148,189 Oligomers of b-aminoxy acids adopt b N–O turns and helical structures by forming a nine memberedring intramolecular hydrogen bond between CQOi and NHi+2, which is further stabilized by another six membered-ring hydrogen bond between NHi+2 and NOi+1 (Fig. 16).148 The b N–O turn shows slight variations in subclasses of b-aminoxy peptides considering the N–O bond position relative to the Ca–Cb bond. For example, the N–O bond is anti-positioned relative to the Ca–Cb bond in b2,2-aminoxy acid-oligomers which adopt 1.79 helix b N–O turns,188 while the N–O bond in b3-aminoxy acid-oligomers can be either anti or gauche to the Ca–Cb bond in

Scheme 8

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both solution and crystalline form depending on the size of substituted side chains.153,190 Also, substitution of a strained ring, (cyclopropyl), on Ca gives b2,2-cyclopropylaminoxy peptides which do not affect b N–O turn and helix structures.191 In acyclic b2,3-aminoxy peptides, the stereochemistry of the substituents has a large effect on folding properties; while syn b2,3-aminoxy peptides prefer the N–O bond gauche to the Ca–Cb bond in solution and crystalline forms, the folding situations are complicated for anti b2,3-aminoxy peptides and non-hydrogen-bonded structures are found in solution and crystalline forms.189 Peptides of trans-b2,3-penta- and hexa-cyclic aminoxy acids adopt 1.89 helix and rigid b N–O turn structures in which the N–O bond is anti to the Ca–Cb bond. Similarly in b2,2aminoxy peptides the b N–O turn structures in cyclic b2,3-aminoxy peptides were found to be independent of the ring size.192 Moreover, peptides derived from cis-b2,3-furanoid sugar aminoxy acids (cis-b-FSAOA) exhibited predominantly gauche conformation around Ca–Cb and featured unusual ribbon-like secondary structures involving 5/7 bifurcated intramolecular hydrogenbonds.193 Different methods were reported for the synthesis of b-aminoxy acids 41. The Mitsunobu reaction was employed for N–O bond installation in b-hydroxycarboxylic acid esters 39 with inversion of chirality at Cb in the synthesis of b2,2 and b2,3-aminoxy acids 41 (Scheme 8).188,189,191 However, in the case of b3-aminoxy acids, Mitsunobu conditions gave the undesired elimination product of an a,b-unsaturated carboxylic acid ester.190 In an alternative strategy designed to prevent a,b-elimination, carboxylic esters were first converted to primary alcohols 42 and protected with the trityl group. After N–O bond installation with N-hydroxyphthalimide under Mitsunobu conditions, primary alcohols 44 were deprotected and oxidized to give N-(Phth)-b3aminoxy acids 41.190 EDCI/HOBt or EDCI/HOAt coupling conditions were preferred in order to link N-phthalimide-protected b-aminoxy peptides.188,190,193 b3-Aminoxy amides 48 were prepared from a-aminoxy acids 46 via Arndt–Eistert homologation (Scheme 9).190 a-Diazoketones 47 derived from a-aminoxy acids 46 underwent the Wolf rearrangement resulting in b-aminoxy amide 48 in the presence of primary amines or b-aminoxy lactams in the absence of amine. b-Aminoxy lactams 49 were treated further with primary amines to obtain b-aminoxy amides 48.190

Synthesis of b-aminoxy acids 41 via Mitsunobu reactions of a-aminoxy acids.

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Scheme 9

Synthesis of b-aminoxy amides 48 via Arndt–Eistert homologation of a-aminoxy acids.

Fig. 17 g-Aminoxy acid and amide with g N–O turn in the X-ray crystal structure (reproduced with permission from ref. 194, J. Am. Chem. Soc., 2004, 126, 15980. Copyright (2004) American Chemical Society.).

g-Aminoxy acids are another example of backbone extended aminoxy acids. Oligomers derived from g-aminoxy acids also form folded secondary structures over ten-membered-ring intramolecular hydrogen bonds, so-called ‘‘g N–O turns’’ between adjacent residues both in solution and in crystalline form (Fig. 17).194,195 The coupling reactions of g-aminoxy acids are usually performed in the presence of EDCI/HOBt (or HOAt) to give g-aminoxy oligomers.195 g-Aminoxy acids were prepared by reaction between N-hydroxyphthalimide and g-hydroxy carboxylic ester under Mitsunobu conditions.195 4.3

a-Hydrazinopeptides and aza-b3-peptides

Hydrazino and aza-b3-peptides, which are derived from the corresponding hydrazino acid precursors, form another class of backbone extended peptidomimetics. Hydrazino acid precursors are aza analogs of b-amino acids with hydrazine functionality where Cb is replaced by nitrogen (Fig. 18).196 However, aza-b3-aminoacids are members of the a-hydrazino acid family bearing an alkyl substituent on the Na atom with ¨nther pyramidal stereogenicity.197 Theoretical calculations by Gu and Hofmann revealed that oligomers of hydrazino acetic acid

Fig. 18

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a-Hydrazino acids and hydrazino N–N turn.

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could feature in a wide variety of peptidic secondary structures and conformers.198 Introduction of an additional nitrogen atom into the amino acid backbone reorganizes the intramolecular hydrogen bonding pattern and promotes the formation of new secondary structures. Oligomers of hydrazino acids induce repetitive bifurcated intramolecular eight-membered hydrogen bonding between COi acceptor and NHi+2 donor. The hydrogen bonding interaction is further stabilized by lone pair participation of neighboring nitrogen atoms (Ni+1), the so called ‘‘hydrazino turn’’ (or N–N turns) (Fig. 18 and 19).197,199 Unlike the traditional E-conformation of a hydrazide linkage, the hydrazino turned hydrazide linkage is forced to adopt a Z-conformation due to the extensive hydrogen bonding network.200 Prominent examples of hydrazino turns appear in 16 and 24 membered macrocycles composed of aza-b3-amino acids (Fig. 20).201–203 Nitrogen is known to undergo rapid pyramidal inversion if it is not a member of small ring. However, the pyramidal Na atom in cyclic aza-b3-peptides can maintain its configuration and chirality by taking part in an intramolecular hydrogen bonding network in repeated hydrazino turns.201–203 The pyramidal inversion of Na atoms in cyclic aza-b3-peptides takes place while undergoing a reversible flip–flop conformational exchange from one possible state to another by overcoming a relatively high inversion barrier.201,203 Le Grel et al. compared the aforementioned flip–flop conformational exchange with chair-tochair transformation in cyclohexane (Fig. 21).203 In the case of linear b3-azapeptides, conformations of linear analogs depend strongly on relative configurations of each pyramidal nitrogen atom in the hydrazino turns. Thus, the linear b3-azapeptides might exist as racemic mixtures consisting of a set of secondary structures with unknown relative populations in solution and crystal form depending on the configuration of the Na atoms.197,199 In 2003, Lelais and Seebach described the preparation of oligomeric hydrazinopeptides from optically pure hydrazinoacids.196 The CD spectra of hexa-b2-azapeptide solutions in MeOH and in H2O indicated the presence of right-handed 314 helical structures.196 However, variable temperature NMR studies in various solvents were not enough to elucidate the secondary structures due to broad, overlapping signals and fast proton exchange rates between NH signals.196 The same study reported, through in vitro experiments, that tri- and hexa-b2-azapeptides were stable against a variety of peptidases for 48 h.196 Despite the interesting conformational features of hydrazinopeptides, applications of these compounds have been limited.

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Fig. 19 Hydrazino N–N turn in the X-ray crystal structure of (a) monomeric,197 (b) dimeric199 and (c) hexameric199 aza-b3-peptide (reproduced with permission from ref. 197, J. Org. Chem., 2006, 71, 150. Copyright (2006) American Chemical Society and ref. 199, J. Org. Chem., 2005, 70, 6499. Copyright (2005) American Chemical Society, respectively).

Fig. 20 H-bond network in the X-ray crystal structure of cyclic (a) tetrameric202 and (b) hexameric203 cyclic aza-b3-peptides (substituents are omitted for clarity) (reproduced with permission from ref. 202, J. Org. Chem., 2008, 73, 8579. Copyright (2008) American Chemical Society and ref. 203, J. Am. Chem. Soc., 2009, 131, 14521. Copyright (2009) American Chemical Society, respectively).

The story of hydrazinopeptides began with incorporation of a-hyrazinocarboxylic acids into peptides in the 1960s by Niedrich et al.204–206 and subsequently Niedrich described the synthesis of hydrazino analogs of an octapeptide, eledoisin.207–212 Linatine, a vitamin B6 antagonist, is the first naturally isolated hydrazinopeptide from linseed consisting of D-hydrazinoproline.213 Negamycine, an antibiotic, isolated from the culture filtrate of Streptomyces purpeofuscus is another natural hydrazino-peptide possessing a strong antimicrobial effect against Gram-negative bacteria.214,215 Carbidopa [(–)-1-2-(3,4dihydroxy-benzyl)-2-hydrazinopropionic acid] is a currently used co-drug (with levodopa) for the treatment of Parkinson’s disease as an inhibitor of peripheral L-aromatic amino acid decarboxylase activity.216,217 Guy et al. previously envisaged a series of

hydrazinohexapeptides as reversible inhibitors of human leukocyte elastase (HLE).218 Recently, incorporation of aza-b3-amino acids into a short marine neuropeptide, originally extracted from cuttlefish Sepia officinalis, resulted in the formation of more rigid peptidomimetic structures with hydrazino turns.219 These modifications changed (positively or negatively) the antimicrobial activity of parental peptide even to the extent of antibacterial activity.219 Similar to azapeptides, construction of hydrazino peptides is based on hydrazine chemistry and starts with the synthesis of a-hydrazinoacid monomers. Herein, we briefly review the preparative methods for hydrazino acid monomers and classify them as (i) addition of the hydrazino part to the a-carbon of a carbonyl compound, and (ii) insertion of an extra amino adjunct by electrophilic amination reactions (Fig. 22). Apart from the above methods, a recent method involving cycloaddition (for N-aminoazetidinecarboxylic acid) has been reported.220,221 One of the classical ways to obtain a-hydrazino carboxylic acid derivatives is by nucleophilic attack of N-protected hydrazines on a-halo-205,222,223 or a-hydroxy-224 carboxylic acids. a-Hydrazinoacid derivatives 53 can be obtained directly by reaction of N-protected hydrazines 50 with the corresponding a-bromocarboxylic acids 51 (Scheme 10),225–228 but, dialkylation products may limit this procedure.229 Recently, in our group, Nb-(free)-a-hydrazinoacids were obtained in 40–48% yields through microwave assisted displacement reactions (70 1C, 50 W, 15–20 min) from chiral a-bromocarboxylic acids.230

Fig. 21 Pyramidal inversion of Na atoms in macrocyclic aza-b3-peptides by a reversible flip–flop conformational exchange (reproduced with permission from ref. 201, J. Org. Chem., 2006, 71, 5638. Copyright (2006) American Chemical Society.).

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Fig. 22 Routes for the preparation of a-hydrazino carboxylic acid derivatives.

A one pot nucleophilic substitution reaction between triflate derivatives of chiral a-hydroxyesters 55 and t-butyl-carbazates 56 gave Boc-protected a-hydrazinoesters 57 with high optical purity, even on a large scale (Scheme 11).224,231 The Mitsunobu protocol has been applied to the synthesis of chiral a-hydrazinoacid derivatives with high optical purity from a-hydroxyesters 54 (Scheme 12).232–234 Free hydrazino acid

Scheme 10

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derivatives 62 were prepared through the deprotection of the phthalimide group 60, and were then converted to Nb-Fmoc- or Nb-Boc-Na-(Cbz)-hydrazinoacid derivatives 63, which were more convenient for SPPS.234 Baudy-Floc’h and co-workers reported a convenient method for the preparation of Nb-Fmoc-substituted aza-b3-amino acids 66 by direct reductive amination of glyoxylic acid-Nb-Fmoc-hydrazones (Scheme 13).227,228,235 In a similar approach, Burk et al. achieved the enantioselective preparation of N-acylhydrazoacids by DuPHOSRh-catalyzed asymmetric hydrogenation of N-acylhydrazones derived from a-ketoesters.236 Asymmetric addition of lithium enolates to the –NQN– double bond of azo compounds resulted in Na,Nb-diprotected a-hydrazinoacid derivatives 68 with high enantiomeric excess (Scheme 14).237–240 In addition, enantioselective Mannich reactions of acylhydrazones with a-aryl silyl ketene acetals in the presence of chiral Lewis acid catalysis gave enantiopure b-hydrazino-acids.241,242

Preparation of Na-(R),Nb-(Fmoc)-protected hydrazino acids 53.

Scheme 11 Preparation of Na-(R 0 ),Nb-(Boc)-protected hydrazino acid derivatives 57.

Scheme 12 Preparation of Na,Nb-(Boc, Cbz or Fmoc)-protected hydrazino acid derivatives 63 via the Mitsunobu protocol.

Scheme 13 Preparation of Na-(R),Nb-(Fmoc)-protected hydrazino acids 66 via reductive amination reaction.

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Scheme 14 Preparation of Na and Nb-(Boc, Cbz)-protected hydrazino acid derivatives 68 via asymmetric addition reactions.

Scheme 15 Preparation of Na-(R 0 ),Nb-(Boc)-protected hydrazino acids 71 through electrophilic amination reaction.

N-Electrophilic amination of enantiomerically pure a-amino acids is a convenient tool to obtain Na,Nb-orthogonally diprotected a-hydrazino acids with high optical purity, even on a multigram scale.196,218,243 Electrophilic amination reactions with N-Boc-oxaziridines 70 enable the conversion of a variety of amino acids 69 to Boc-protected hydrazinoacids 71 (Scheme 15).243 Furthermore, Melnyk and co-workers described a facile installation of the hydrazino functionality into amino acids in the solid phase by N-electrophilic amination with N-Boc-3(4-cyanophenyl)oxaziridine (BCPO).244–246 Recently, N-Boc-Otosylhydroxylamine has proved to be a NH-Boc transfer reagent by converting chiral amino acids to Boc-protected hydrazino acids.247 Reduction of Na-nitrosoamino acids213,248,249 and rearrangement of the hydantoic acids250,251 are alternative access routes to hydrazinoacids from amino acids. Apart from the methods outlined above, Aitken and co-workers recently described the first synthesis of ()-N-aminoazetidinecarboxylic acid 74, a small-ring containing hydrazinoacid, by photochemical [2+2] cycloaddition of ethylene 72 to 6-azauracli 73 (Scheme 16).220 Enantiomers 74a and 74b formed by the cycloaddition reaction were resolved by chiral derivatization with (S)-4-benzyloxazolidin-2-one.220 However, attempts to form oligopeptides by reactions of the N-terminus of 1-aminoazetidine-2carboxylic acid 74b could not be achieved by classical peptide coupling reagents (DCC, EDCI, FDPP, HATU, HBTU) and only the use of IBCF/NMM in THF gave dipeptide 76 by a ring opening process.221

Scheme 16

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From the beginning of the discovery of hydrazino peptides, many synthetic methods for the hydrazide linkage have been reported. Typically, natural peptide coupling systems are suitable for hydrazinoacid couplings. The proven methods for the hydrazide linkage include the use of coupling reagents such as DCC/DMAP,252,253 EDCI/HOBt,224 DIC,229 DIC/HOBt,227 HATU/NMM,231 HBTU/HOBt/DIEA,229 BOP/DIEA,246 activated esters (OSu),218,229,246,254 mixed anhydrides,218 acid chlorides254 fluorides234,255 and N-(acyl)benzotriazoles.230 In fact, the critical factor in obtaining hydrazino compounds is regioselectivity. Since the adjacent nitrogen atoms (Na and Nb) are both reactive, differentiation of these nitrogen atoms is necessary.218,227,229,256 While preparing hydrazinopeptides as human leukocyte elastase (HLE) inhibitors, Guy et al. encountered the formation of side reactions related to regioselectivity, when Na-unprotected, Nb-(Boc)-hydrazinoacids were coupled with N-free peptide derivatives. To circumvent this problem, they used Na-(Bzl),Nb-(Boc)bisprotected hydrazino acids.218 On the other hand, coupling of N-protected aminoacid with Na,Nb-unprotected hydrazinoacids occurs regioselectively on the b-nitrogen atom if both have bulky side chains.218 Hydrazinopeptides were also prepared on a solid phase from the corresponding Boc and Fmoc protected hydrazinoacids.227,229,255

5. Conclusion Although natural peptides provide high levels of biodiversity, biological activity, specificity and low toxicity in therapeutic uses, they suffer from lack of bioavailability, low stability due to rapid protease degradation, difficulties during passage through the cell membrane and challenging multistep preparations. During the last two decades, peptidomimetics have evolved to eliminate the limitations of native peptides in therapeutic use. Peptidomimetics can be accessed by manipulations of the amino acid backbone of native peptides. Such manipulations enrich structural diversity and create novel peptidomimetics having particular secondary structures and pharmacological properties. Herein, we have outlined recent developments in peptidomimetics that were formed via hetero atom replacement or insertion into the amino acid backbone. Most peptidomimetics discussed form structural organizations such as turns, helices, sheets and loops via non-covalent interactions. For example, a-aminoxypeptides are distinguished with a N–O turns, while

Synthesis and reactivity of ()-N-aminoazetidinecarboxylic acid 74.

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b-aminoxypeptides and hydrazinopeptides feature b N–O turns and N–N hydrazino turns, respectively. Furthermore, macrocyclic hydrazinopeptides (aza-b3-peptides) preserve the stereo configuration of the Na atom in their backbone by intramolecular hydrogen bonding in repetitive N–N hydrazino turns. Heteroatom manipulations affect the structural rigidity-flexibility relative to native peptides by altering H-bonding abilities. For example azapeptides are rigid due to Ca replacement by a nitrogen atom, whereas depsipeptides are more flexible by loss of NH as a H-bond donor. Chemical reactivity is also affected by heteroatom replacement as in thiodepsipeptides which are subject to native chemical ligation (NCL). Heteroatommodified peptides are also the subject of structure–activity relationship (SAR) studies and some have found significant clinical use as FDA-approved drugs, such as romidepsin (Istodaxt), atazanavir (Reyatazt) and bortezomib (Velcadet). Bortezomib, formed via carbonyl replacement by boronic acid, is a proteasome inhibitor for the treatment of progressive multiple myeloma.257,258 Structureactivity relationships and structural, conformational analyses pave the way for establishing peptidomimetic libraries which may lead to the creation of novel medicines and materials. Thus, recent developments indicate that peptidomimetics are likely to afford extraordinary applications in therapeutic and material fields.

Abbreviations Acm ALA BCPO Boc BOP

Acetamidomethyl 5-Aminolaevulinic acid N-Boc-3-(4-cyanophenyl)oxaziridine t-Butyloxycarbonyl Benzotriazol-1-yloxytris(dimethylamino)phosphornium hexafluorophosphate BOP-Cl N,N 0 -Bis(2-oxo-3-oxazolidinyl)phosphinic chloride BTE Backbone thioester exchange Cbz Benzyloxycarbonyl CD Circular dichroism CDI N,N 0 -Carbonyldiimidazole cis-b-FSAOA cis-b2,3-Furanoid sugar aminoxy acids CPP Cell-penetrating peptides DCC N,N 0 -Dicyclohexylcarbodiimide Ddz a,a-Dimethyl-3,5-dimethoxybenzyloxycarbonyl de Diastereomeric excess DIAD Diisopropyl azodicarboxylate DIC N,N 0 -diisopropylcarbodiimide DBAD Di-tert-butyl azodicarboxylate DEAD Diethyl azodicarboxylate DIEA N,N-Diisopropylethylamine (DIPEA) DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DNA Deoxyribonucleic acid DuPHOS 1,2-Bis(2,5-dialkylphospholano)benzene EDCI 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride ee Enantiomeric excess FDA Food and Drug Administration FDPP Pentafluorophenyl diphenyl phosphinate

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Fmoc GHRP-6 HATU HAV HBTU hCGRP HCTU HIV HLE HOAt HOBt IBCF LDA NCL NEM NMM NMR PAM Pg Phth PKB/Akt PS-PEG p-TSA PyBOP PyBroP RNA SAR sp. SPPS TBTU TCBC Tce TES Tf TFA THF THP TNTU tPNA Trt TSTU

9-Fluorenylmethyloxcarbonyl Growth hormone releasing peptide-6 O-(7-Azabenzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate Hepatitis A virus O-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate Human calcitonin gene-related peptide 1H-Benzotriazolium 1-[bis(dimethyl-amino)methylene]-5-chloro-hexafluorophosphate (1-),3-oxide Human immunodeficiency virus Human leukocyte elastase 1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole Isobutyl chloroformate Lithium diisopropylamide Native chemical ligation N-Ethylmorpholine N-Methylmorpholine Nuclear magnetic resonance Peptidylglycine a-amidating monooxygenase Protecting group Phthaloyl Protein kinase B Polystyrene-polyethylene glycol resin p-Toluenesulfonic acid Benzotriazol-1-yloxytri(pyrrolidino) phosphonium hexafluorophosphate Bromotri(pyrrolidino)phosphonium hexafluorophosphate Ribonucleic acid Structure-activity relationship Species Solid phase peptide synthesis O-Benzotriazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate 2,4,6-Trichlorobenzoyl chloride 2,2,2-Trichloroethyl Triethylsilane Triflyl (trifluoromethanesulfonyl) Trifluoroacetic acid Tetrahydrofuran Tetrahydropyranyl 2-(5-Norbornene-2,3-dicarboximido)-1,1,3,3tetramethyluronium tetrafluoroborate Thioester peptide nucleic acid Trityl (triphenylmethyl) 2-Succinimido-1,1,3,3-tetramethyluroniumtetrafluoroborate

Acknowledgements ¨ktu ¨lbakan, Mr E. Go ¨rk and Mr Z. We thank Dr B. Inci, Dr B. Gu Topalcengiz for helpful discussions.

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Peptidomimetics via modifications of amino acids and peptide bonds.

Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptide...
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