Azapeptides -A History of Synthetic Milestones and Key Examples

Kai      Fan Cheng; Sonya      VanPatten; Mingzhu      He; Yousef      Al-Abed
Abstract

For over 50 years of azapeptide synthetic techniques, developments have renewed the field of peptidomimetic therapeutics. Azapeptides are close surrogates of natural peptides: they contain a substitution of the amino acid α-carbon by a nitrogen atom. Goserelin (1989) and Atazanavir (2003) are two well-known, FDA-approved azapeptide-based drugs for the treatment of cancers and HIV infection, providing evidence for the successful clinical implementation of this class of therapeutic. This review highlights the azapeptides in recent medicinal chemistry applications and synthetic milestones. We describe the current techniques for azapeptide bond formation by introducing azapeptide coupling reagents and chain elongation methods both in solution and solid-phase strategies.
Keywords: Azapeptides, peptidomimetic, peptide therapeutic, building blocks, carbonyl activating reagents, peptide synthesis, solid-phase peptide synthesis (SPPS), submonomer synthesis, azapeptide scanning.
[1] 
Gante, J. Azapeptides. Synthesis,  1989, 21(06), 405-413.
[http://dx.doi.org/10.1055/s-1989-27269] 
[2] 
Zega, A. Azapeptides as pharmacological agents. Curr. Med. Chem.,  2005, 12(5), 589-597.
[PMID:  15777214] 
[3] 
Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; García Ramos, Y.; Lubell, W.D. Azapeptides and their therapeutic potential. Future Med. Chem.,  2011, 3(9), 1139-1164.
[http://dx.doi.org/10.4155/fmc.11.74] [PMID:  21806378] 
[4] 
Jamieson, A.G.; Boutard, N.; Sabatino, D.; Lubell, W.D. Peptide scanning for studying structure-activity relationships in drug discov-ery. Chem. Biol. Drug Des.,  2013, 81(1), 148-165.
[http://dx.doi.org/10.1111/cbdd.12042] [PMID:  23253136] 
[5] 
Avan, I.; Hall, C.D.; Katritzky, A.R. Peptidomimetics via modifications of amino acids and peptide bonds. Chem. Soc. Rev.,  2014, 43(10), 3575-3594.
[http://dx.doi.org/10.1039/c3cs60384a] [PMID:  24626261] 
[6] 
Jílková, A.; Horn, M.; Fanfrlík, J.; Küppers, J.; Pachl, P.; Řezáčová, P.; Lepšík, M.; Fajtová, P.; Rubešová, P.; Chanová, M.; Caffrey, C.R.; Gütschow, M.; Mareš, M. Azanitrile inhibitors of the SmCB1 protease target are lethal to Schistosoma mansoni: Structural and mechanistic insights into chemotype reactivity. ACS Infect. Dis.,  2021, 7(1), 189-201.
[http://dx.doi.org/10.1021/acsinfecdis.0c00644] [PMID:  33301315] 
[7] 
Arifa Begum, D.S.; Prasad, K.V.S.R.G.; Bharathi, K. A review on azapeptides: The promising peptidomimetics. Asian J. Chem.,  2017, 29(9), 1879-1887.
[http://dx.doi.org/10.14233/ajchem.2017.20802] 
[8] 
O’Donnell, M.J.; Zhou, C.; Scott, W.L. Solid-phase unnatural peptide synthesis (UPS). J. Am. Chem. Soc.,  1996, 118(25), 6070-6071.
[http://dx.doi.org/10.1021/ja9601245] 
[9] 
Lee, H-J.; Park, H-M.; Lee, K-B. The β-turn scaffold of tripeptide containing an azaphenylalanine residue. Biophys. Chem.,  2007, 125(1), 117-126.
[http://dx.doi.org/10.1016/j.bpc.2006.05.028] [PMID:  16890344] 
[10] 
Hemmerlin, C.; Cung, M.T.; Boussard, G. Synthesis and conformational preferences in solution and crystalline states of an aza-tripeptide. Tetrahedron Lett.,  2001, 42(30), 5009-5012.
[http://dx.doi.org/10.1016/S0040-4039(01)00917-0] 
[11] 
André, F.; Marraud, M.; Boussard, G.; Didierjean, C.; Aubry, A. Synthesis and structure of AzAsx-Pro-containing Aza-peptides. Tetrahedron Lett.,  1996, 37(2), 183-186.
[http://dx.doi.org/10.1016/0040-4039(95)02124-8] 
[12] 
Benatalah, Z.; Aubry, A.; Boussard, G.; Marraud, M. Evidence for a β-turn in an azadipeptide sequence. Synthesis and crystal structure of ButCO-Pro-AzaAla-NHPri. Int. J. Pept. Protein Res.,  1991, 38(6), 603-605.
[http://dx.doi.org/10.1111/j.1399-3011.1991.tb01547.x] [PMID:  1819595] 
[13] 
Hsieh, A.H.C.; Kichenadasse, G.; Vatandoust, S.; Roy, A.; Sukumaran, S.; Karapetis, C.S.; Martin, H.; Chong, L.C.; Koczwara, B. Goserelin toxicities and preferences for ovarian suppression method in pre-menopausal women with breast cancer. Intern. Med. J.,  2016, 46(10), 1153-1159.
[http://dx.doi.org/10.1111/imj.13169] [PMID:  27389059] 
[14] 
Boccardo, F.; Barichello, M.; Battaglia, M.; Carmignani, G.; Comeri, G.; Ferraris, V.; Lilliu, S.; Montefiore, F.; Portoghese, F.; Cortelli-ni, P.; Rigatti, P.; Usai, E.; Rubagotti, A.; Ferraris, V.; Muzzonigro, G.; Di Santo, V.; Selvaggi, F.P.; Borin, D.; Lilliu, S.; Usai, E.; Dammino, S.; Salvia, G.; Consoli, C.; Motta, M.; Comeri, G.; Rizzo, M.; Pellegrino, A.; Fabbri, F.; Boccardo, F.; Carmignani, G.; Pao-lini, R.; Cruciani, G.; Santelli, G.; Rigatti, P.; Malagola, G.; Ferrari, P.; Montefiore, F.; Pinna, A.; Piazza, B.; Pavone, M.; Cortellini, P.; Porena, M.; Giannotti, P.; Muzzarelli, M.; Alcini, E.; De Carli, P.; Bercovich, E.; Epis, R.; Andreassi, F.; Bono, A.V. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer: Updated results of a multicentric trial. Eur. Urol.,  2002, 42(5), 481-490.
[http://dx.doi.org/10.1016/S0302-2838(02)00435-9] [PMID:  12429158] 
[15] 
Taylor, C.W.; Green, S.; Dalton, W.S.; Martino, S.; Rector, D.; Ingle, J.N.; Robert, N.J.; Budd, G.T.; Paradelo, J.C.; Natale, R.B.; Bearden, J.D.; Mailliard, J.A.; Osborne, C.K. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premeno-pausal patients with receptor-positive metastatic breast cancer: An intergroup study. J. Clin. Oncol.,  1998, 16(3), 994-999.
[http://dx.doi.org/10.1200/JCO.1998.16.3.994] [PMID:  9508182] 
[16] 
Tyrrell, C.J.; Altwein, J.E.; Klippel, F.; Varenhorst, E.; Lunglmayr, G.; Boccardo, F.; Holdaway, I.M.; Haefliger, J.M.; Jordaan, J.P.; Sotarauta, M. A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J. Urol.,  1991, 146(5), 1321-1326.
[http://dx.doi.org/10.1016/S0022-5347(17)38080-1] [PMID:  1834864] 
[17] 
Piliero, P.J. Atazanavir: A novel HIV-1 protease inhibitor. Expert Opin. Investig. Drugs,  2002, 11(9), 1295-1301.
[http://dx.doi.org/10.1517/13543784.11.9.1295] [PMID:  12225250] 
[18] 
Hess, H-J.; Moreland, W.T.; Laubach, G.D.N. - [2-Isopropyl-3-(L-aspartyl-L-arginyl)-carbazoyl]-L- tyrosyl-L-valyl-L-histidyl-L-prolyl-L-phenylalanine,1 an isostere of bovine angiotensin II. J. Am. Chem. Soc.,  1963, 85(24), 4040-4041.
[http://dx.doi.org/10.1021/ja00907a036] 
[19] 
Niedrich, H.; Oehme, C. Hydrazine compounds as hetero-components in peptides. XV. Synthesis of eledoisin octapeptides with the carbazyl residues azaglycine and α-azaasparagine instead of glycine and asparagine. J. Prakt. Chem.,  1972, 314, 759-768.
[http://dx.doi.org/10.1002/prac.19723140508] 
[20] 
Niedrich, H.; Oehme, C.; Bergmann, J. Hydrazine compounds as hetero-components in peptides. XIX. Eledoisin peptides containing the N2-methylcarbazoyl radical (azaalanine). J. Prakt. Chem.,  1974, 316, 741-749.
[http://dx.doi.org/10.1002/prac.19743160505] 
[21] 
Oehme, P.; Bergmann, J.; Falck, M.; Reich, J.G.; Vogt, W.E.; Niedrich, H.; Pirrwitz, J.; Berseck, C.; Jung, F. Pharmacology of hydra-zino carbonic acids, hydrazino peptides and other hydrazine derivatives. Structure-action studies in heterologeous eledoisin octapeptide sequences. Acta Biol. Med. Ger.,  1972, 28(1), 109-120.
[PMID:  5065473] 
[22] 
Dutta, A.S.; Furr, B.J.; Giles, M.B.; Morley, J.S. Synthesis and biological activity of alpha-azapeptides: Alpha-aza-analogues of luteiniz-ing hormone releasing hormone. Clin. Endocrinol. (Oxf.),  1976, 5(s1)(Suppl.), 291S-298S.
[http://dx.doi.org/10.1111/j.1365-2265.1976.tb03837.x] [PMID:  802685] 
[23] 
Dutta, A.S.; Gormley, J.J.; Hayward, C.F.; Morley, J.S.; Shaw, J.S.; Stacey, G.J.; Turnbull, M.T. Enkephalin analogues eliciting anal-gesia after intravenous injection. Life Sci.,  1977, 21(4), 559-562.
[http://dx.doi.org/10.1016/0024-3205(77)90097-2] [PMID:  904434] 
[24] 
Gacel, G.; Zajac, J.M.; Delay-Goyet, P.; Daugé, V.; Roques, B.P. Investigation of the structural parameters involved in the Mu and delta opioid receptor discrimination of linear enkephalin-related peptides. J. Med. Chem.,  1988, 31(2), 374-383.
[http://dx.doi.org/10.1021/jm00397a019] [PMID:  2828622] 
[25] 
Han, H.; Yoon, J.; Janda, K.D. Investigations of azapeptides as mimetics of Leu-enkephalin. Bioorg. Med. Chem. Lett.,  1998, 8(1), 117-120.
[http://dx.doi.org/10.1016/S0960-894X(97)10198-6] [PMID:  9871637] 
[26] 
Sulyok, G.A.G.; Gibson, C.; Goodman, S.L.; Hölzemann, G.; Wiesner, M.; Kessler, H. Solid-phase synthesis of a nonpeptide RGD mimetic library: New selective alphavbeta3 integrin antagonists. J. Med. Chem.,  2001, 44(12), 1938-1950.
[http://dx.doi.org/10.1021/jm0004953] [PMID:  11384239] 
[27] 
Spiegel, J.; Mas-Moruno, C.; Kessler, H.; Lubell, W.D. Cyclic aza-peptide integrin ligand synthesis and biological activity. J. Org. Chem.,  2012, 77(12), 5271-5278.
[http://dx.doi.org/10.1021/jo300311q] [PMID:  22582818] 
[28] 
Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C.B.; Boeglin, D.; Ong, H.; Lubell, W.D. Exploring side-chain diversity by submonomer solid-phase aza-peptide synthesis. Org. Lett.,  2009, 11(16), 3650-3653.
[http://dx.doi.org/10.1021/ol901423c] [PMID:  19606817] 
[29] 
Sabatino, D.; Proulx, C.; Pohankova, P.; Ong, H.; Lubell, W.D. Structure-activity relationships of GHRP-6 azapeptide ligands of the CD36 scavenger receptor by solid-phase submonomer azapeptide synthesis. J. Am. Chem. Soc.,  2011, 133(32), 12493-12506.
[http://dx.doi.org/10.1021/ja203007u] [PMID:  21692501] 
[30] 
Proulx, C.; Picard, É.; Boeglin, D.; Pohankova, P.; Chemtob, S.; Ong, H.; Lubell, W.D. Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a. J. Med. Chem.,  2012, 55(14), 6502-6511.
[http://dx.doi.org/10.1021/jm300557t] [PMID:  22712585] 
[31] 
Proulx, C.; Zhang, J.; Sabatino, D.; Chemtob, S.; Ong, H.; Lubell, W.D. Synthesis and biomedical potential of azapeptide modulators of the cluster of differentiation 36 receptor (CD36). Biomedicines,  2020, 8(8), 241.
[http://dx.doi.org/10.3390/biomedicines8080241] [PMID:  32717955] 
[32] 
Ohm, R.G.; Mulumba, M.; Chingle, R.M. Ahsanullah; Zhang, J.; Chemtob, S.; Ong, H.; Lubell, W.D. Diversity-oriented A3-macrocyclization for studying influences of ring-size and shape of cyclic peptides: CD36 receptor modulators. J. Med. Chem.,  2021, 64(13), 9365-9380.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00642] [PMID:  34161728] 
[33] 
Zhao, Z.; Zhang, M.; Tang, B.; Weng, P.; Zhang, Y.; Yan, X.; Li, Z.; Jiang, Y-B. Transmembrane fluoride transport by a cyclic azapep-tide with two β-turns. Front Chem.,  2021, 8(1206)621323
[http://dx.doi.org/10.3389/fchem.2020.621323] [PMID:  33511101] 
[34] 
Boeglin, D.; Xiang, Z.; Sorenson, N.B.; Wood, M.S.; Haskell-Luevano, C.; Lubell, W.D. Aza-scanning of the potent melanocortin re-ceptor agonist Ac-His-D-Phe-Arg-Trp-NH. Chem. Biol. Drug Des.,  2006, 67(4), 275-283.
[http://dx.doi.org/10.1111/j.1747-0285.2006.00378.x] [PMID:  16629825] 
[35] 
Boeglin, D.; Hamdan, F.F.; Melendez, R.E.; Cluzeau, J.; Laperriere, A.; Héroux, M.; Bouvier, M.; Lubell, W.D. Calcitonin gene-related peptide analogues with aza and indolizidinone amino acid residues reveal conformational requirements for antagonist activity at the hu-man calcitonin gene-related peptide 1 receptor. J. Med. Chem.,  2007, 50(6), 1401-1408.
[http://dx.doi.org/10.1021/jm061343w] [PMID:  17319653] 
[36] 
Kurian, L.A.; Silva, T.A.; Sabatino, D. Submonomer synthesis of azapeptide ligands of the Insulin Receptor Tyrosine Kinase domain. Bioorg. Med. Chem. Lett.,  2014, 24(17), 4176-4180.
[http://dx.doi.org/10.1016/j.bmcl.2014.07.046] [PMID:  25127870] 
[37] 
Magrath, J.; Abeles, R.H. Cysteine protease inhibition by azapeptide esters. J. Med. Chem.,  1992, 35(23), 4279-4283.
[http://dx.doi.org/10.1021/jm00101a004] [PMID:  1447732] 
[38] 
Asgian, J.L.; James, K.E.; Li, Z.Z.; Carter, W.; Barrett, A.J.; Mikolajczyk, J.; Salvesen, G.S.; Powers, J.C. Aza-peptide epoxides: A new class of inhibitors selective for clan CD cysteine proteases. J. Med. Chem.,  2002, 45(23), 4958-4960.
[http://dx.doi.org/10.1021/jm025581c] [PMID:  12408706] 
[39] 
James, K.E.; Asgian, J.L.; Li, Z.Z.; Ekici, Ö.D.; Rubin, J.R.; Mikolajczyk, J.; Salvesen, G.S.; Powers, J.C. Design, synthesis, and eval-uation of aza-peptide epoxides as selective and potent inhibitors of caspases-1, -3, -6, and -8. J. Med. Chem.,  2004, 47(6), 1553-1574.
[http://dx.doi.org/10.1021/jm0305016] [PMID:  14998341] 
[40] 
Ekici, Ö.D.; Götz, M.G.; James, K.E.; Li, Z.Z.; Rukamp, B.J.; Asgian, J.L.; Caffrey, C.R.; Hansell, E.; Dvorák, J.; McKerrow, J.H.; Potempa, J.; Travis, J.; Mikolajczyk, J.; Salvesen, G.S.; Powers, J.C. Aza-peptide Michael acceptors: A new class of inhibitors specific for caspases and other clan CD cysteine proteases. J. Med. Chem.,  2004, 47(8), 1889-1892.
[http://dx.doi.org/10.1021/jm049938j] [PMID:  15055989] 
[41] 
Ekici, Ö.D.; Li, Z.Z.; Campbell, A.J.; James, K.E.; Asgian, J.L.; Mikolajczyk, J.; Salvesen, G.S.; Ganesan, R.; Jelakovic, S.; Grütter, M.G.; Powers, J.C. Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10. J. Med. Chem.,  2006, 49(19), 5728-5749.
[http://dx.doi.org/10.1021/jm0601405] [PMID:  16970398] 
[42] 
Ganesan, R.; Jelakovic, S.; Campbell, A.J.; Li, Z.Z.; Asgian, J.L.; Powers, J.C.; Grütter, M.G. Exploring the S4 and S1 prime subsite specificities in caspase-3 with aza-peptide epoxide inhibitors. Biochemistry,  2006, 45(30), 9059-9067.
[http://dx.doi.org/10.1021/bi060364p] [PMID:  16866351] 
[43] 
Sexton, K.B.; Kato, D.; Berger, A.B.; Fonovic, M.; Verhelst, S.H.L.; Bogyo, M. Specificity of aza-peptide electrophile activity-based probes of caspases. Cell Death Differ.,  2007, 14(4), 727-732.
[http://dx.doi.org/10.1038/sj.cdd.4402074] [PMID:  17170749] 
[44] 
Götz, M.G.; James, K.E.; Hansell, E.; Dvorák, J.; Seshaadri, A.; Sojka, D.; Kopácek, P.; McKerrow, J.H.; Caffrey, C.R.; Powers, J.C. Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolu-tionarily diverse pathogens. J. Med. Chem.,  2008, 51(9), 2816-2832.
[http://dx.doi.org/10.1021/jm701311r] [PMID:  18416543] 
[45] 
Ovat, A.; Muindi, F.; Fagan, C.; Brouner, M.; Hansell, E.; Dvorák, J.; Sojka, D.; Kopácek, P.; McKerrow, J.H.; Caffrey, C.R.; Powers, J.C. Aza-peptidyl Michael acceptor and epoxide inhibitors--potent and selective inhibitors of Schistosoma mansoni and Ixodes ricinus legumains (asparaginyl endopeptidases). J. Med. Chem.,  2009, 52(22), 7192-7210.
[http://dx.doi.org/10.1021/jm900849h] [PMID:  19848405] 
[46] 
Semple, J.E.; Rowley, D.C.; Brunck, T.K.; Ripka, W.C. Synthesis and biological activity of P2–P4 azapeptidomimetic P1-argininal and P1-ketoargininamide derivatives: A novel class of serine protease inhibitors. Bioorg. Med. Chem. Lett.,  1997, 7(3), 315-320.
[http://dx.doi.org/10.1016/S0960-894X(97)00005-X] 
[47] 
Randolph, J.T.; Zhang, X.; Huang, P.P.; Klein, L.L.; Kurtz, K.A.; Konstantinidis, A.K.; He, W.; Kati, W.M.; Kempf, D.J. Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor. Bioorg. Med. Chem. Lett.,  2008, 18(8), 2745-2750.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.053] [PMID:  18375121] 
[48] 
Pérez-Elías, M.J. Atazanavir: Simplicity and convenience in different scenarios. Expert Opin. Pharmacother.,  2007, 8(5), 689-700.
[http://dx.doi.org/10.1517/14656566.8.5.689] [PMID:  17376023] 
[49] 
Zamora, L.; Gatell, J.M. Atazanavir en el tratamiento de simplificación. Enferm. Infecc. Microbiol. Clin.,  2008, 26(Suppl. 17), 14-21.
[http://dx.doi.org/10.1016/S0213-005X(08)76615-1] [PMID:  20116612] 
[50] 
Inagaki, I.; Adachi, M.; Ito, H.; Yasuda, M.; Tsurumi, H.; Deguchi, T.; Seishima, M. Atazanavir-induced urine crystals demonstrated by infrared spectroscopic analysis. Urol. Int.,  2015, 94(1), 121-124.
[http://dx.doi.org/10.1159/000354735] [PMID:  24334974] 
[51] 
Melton, S.D.; Brackhahn, E.A.E.; Orlin, S.J.; Jin, P.; Chenoweth, D.M. Rules for the design of aza-glycine stabilized triple-helical colla-gen peptides. Chem. Sci. (Camb.),  2020, 11(39), 10638-10646.
[http://dx.doi.org/10.1039/D0SC03003A] [PMID:  34094319] 
[52] 
Breidenbach, J.; Lemke, C.; Pillaiyar, T.; Schäkel, L.; Al Hamwi, G.; Diett, M.; Gedschold, R.; Geiger, N.; Lopez, V.; Mirza, S.; Na-masivayam, V.; Schiedel, A.C.; Sylvester, K.; Thimm, D.; Vielmuth, C.; Phuong Vu, L.; Zyulina, M.; Bodem, J.; Gütschow, M.; Mül-ler, C.E. Targeting the main protease of SARS-CoV-2: From the establishment of high throughput screening to the design of tailored in-hibitors. Angew. Chem.,  2021, 60(18), 10423-10429.
[53] 
Corrigan, T.S.; Lotti Diaz, L.M.; Border, S.E.; Ratigan, S.C.; Kasper, K.Q.; Sojka, D.; Fajtova, P.; Caffrey, C.R.; Salvesen, G.S.; McElroy, C.A.; Hadad, C.M.; Doğan Ekici, Ö. Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors. J. Enzyme Inhib. Med. Chem.,  2020, 35(1), 1387-1402.
[http://dx.doi.org/10.1080/14756366.2020.1781107] [PMID:  32633155] 
[54] 
Stollé, R. Hydrazi-dicarbon-hydrazid. Ber. Dtsch. Chem. Ges.,  1910, 43(2), 2468-2470.
[http://dx.doi.org/10.1002/cber.191004302216] 
[55] 
Gante, J.; Lautsch, W. Enzyme models. XLVI. Peptide-like systems. 1. α-(4-Semicarbazino)fatty acid groups as building units of novel oligo compounds. Chem. Ber.,  1964, 97, 983-988.
[http://dx.doi.org/10.1002/cber.19640970408] 
[56] 
Ronco, K.; Prijs, B.; Erlenmeyer, H.; Aminosäure-Analoge aus der Hydrazinreihe, I.I. Aminosäure-Analoge aus der Hydrazinreihe II. Helv. Chim. Acta,  1956, 39(5), 1253-1257.
[http://dx.doi.org/10.1002/hlca.19560390512] 
[57] 
Quibell, M.; Turnell, W.G.; Johnson, T. Synthesis of azapeptides by the Fmoc/tert-butyl/polyamide technique. J. Chem. Soc., Perkin Trans. 1,  1993, (22), 2843-2849.
[http://dx.doi.org/10.1039/p19930002843] 
[58] 
Gibson, C.; Goodman, S.L.; Hahn, D.; Hölzemann, G.; Kessler, H. Novel solid-phase synthesis of azapeptides and azapeptoides via fmoc-strategy and its application in the synthesis of RGD-Mimetics. J. Org. Chem.,  1999, 64(20), 7388-7394.
[http://dx.doi.org/10.1021/jo9906173] 
[59] 
Melendez, R.E.; Lubell, W.D. Aza-amino acid scan for rapid identification of secondary structure based on the application of N-Boc-aza(1)-dipeptides in peptide synthesis. J. Am. Chem. Soc.,  2004, 126(21), 6759-6764.
[http://dx.doi.org/10.1021/ja039643f] [PMID:  15161304] 
[60] 
Kato, D.; Verhelst, S.H.L.; Sexton, K.B.; Bogyo, M. A general solid phase method for the preparation of diverse azapeptide probes di-rected against cysteine proteases. Org. Lett.,  2005, 7(25), 5649-5652.
[http://dx.doi.org/10.1021/ol052275v] [PMID:  16321013] 
[61] 
Dutta, A.S.; Morley, J.S. Polypeptides. Part XIII. Preparation of [small alpha]-aza-amino-acid (carbazic acid) derivatives and intermedi-ates for the preparation of [small alpha]-aza-peptides. J. Chem. Soc., Perkin Trans. 1,  1975, (17), 1712-1720.
[http://dx.doi.org/10.1039/P19750001712] 
[62] 
Biel, J.H.; Drukker, A.E.; Mitchell, T.F.; Sprengeler, E.P.; Nuhfer, P.A.; Conway, A.C.; Horita, A. Central stimulants. Chemistry and structure-activity relationship of aralkyl hydrazines. J. Am. Chem. Soc.,  1959, 81(11), 2805-2813.
[http://dx.doi.org/10.1021/ja01520a048] 
[63] 
Janda, K.D.; Han, H. Azatide peptidomimetics. Patent
WO9735199A1. 1997.
[64] 
Boeglin, D.; Lubell, W.D. Aza-amino acid scanning of secondary structure suited for solid-phase peptide synthesis with fmoc chemistry and aza-amino acids with heteroatomic side chains. J. Comb. Chem.,  2005, 7(6), 864-878.
[http://dx.doi.org/10.1021/cc050043h] [PMID:  16283795] 
[65] 
Freeman, N.S.; Hurevich, M.; Gilon, C. Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase syn-thesis of aza-peptides. Tetrahedron,  2009, 65(8), 1737-1745.
[http://dx.doi.org/10.1016/j.tet.2008.11.038] 
[66] 
Abbas, C.; Pickaert, G.; Didierjean, C.; Grégoire, B.J.; Vanderesse, R. Original and efficient synthesis of 2:1-[α/aza]-oligomer precur-sors. Tetrahedron Lett.,  2009, 50(28), 4158-4160.
[http://dx.doi.org/10.1016/j.tetlet.2009.04.131] 
[67] 
Casarini, M.E.; Ghelfi, F.; Libertini, E.; Pagnoni, U.M.; Parsons, A.F. 1,2-Reduction of α,β-unsaturated hydrazones using dimethyla-mine–borane/p-toluenesulfonic acid: An easy route to allyl hydrazines. Tetrahedron,  2002, 58(39), 7925-7932.
[http://dx.doi.org/10.1016/S0040-4020(02)00914-6] 
[68] 
Gagné-Monfette, W.; Vincent-Rocan, J-F.; Lutes, O.C.; O’Keefe, G.F.; Jeanneret, A.D.M.; Blanger, C.; Ivanovich, R.A.; Beauchemin, A.M. Investigation of masked N-acyl-N-isocyanates: Support for oxadiazolones as blocked N-isocyanate precursors. Chemistry,  2021, 27(56), 14051-14056.
[http://dx.doi.org/10.1002/chem.202102301] [PMID:  34406683] 
[69] 
Zhang, J.; Mulumba, M.; Ong, H.; Lubell, W.D. Diversity-oriented synthesis of cyclic azapeptides by A3 -macrocyclization provides high-affinity CD36-modulating peptidomimetics. Angew. Chem. Int. Ed. Engl.,  2017, 56(22), 6284-6288.
[http://dx.doi.org/10.1002/anie.201611685] [PMID:  28090719] 
[70] 
Ahsanullah; Chingle, R.; Ohm, R.G.; Chauhan, P.S.; Lubell, W.D. Aza-propargylglycine installation by aza-amino acylation: Synthesis and Ala-scan of an azacyclopeptide CD36 modulator. Pept. Sci. (Hoboken),  2019, 111(1)e24102
[71] 
André, F.; Marraud, M.; Tsouloufis, T.; Tzartos, S.J.; Boussard, G. Triphosgene: An efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide. J. Pept. Sci.,  1997, 3(6), 429-441.
[http://dx.doi.org/10.1002/(SICI)1099-1387(199711)3:6<429:AID-PSC115>3.0.CO;2-C] [PMID:  9467971] 
[72] 
Frochot, C.; Vanderesse, R.; Driou, A.; Linden, G.; Marraud, M.; Cung, M.T. A solid-phase synthesis of three aza-, iminoaza- and re-duced aza-peptides from the same precursor. Lett. Pept. Sci.,  1997, 4(4), 219-225.
[http://dx.doi.org/10.1007/BF02442879] 
[73] 
Staab, H.A. New methods of preparative organic chmistry IV. Syntheses using heterocyclic amides (Azolides). Angew. Chem. Int. Ed. Engl.,  1962, 1(7), 351-367.
[http://dx.doi.org/10.1002/anie.196203511] 
[74] 
Wieczerzak, E.; Drabik, P.; Łankiewicz, L.; Ołdziej, S.; Grzonka, Z.; Abrahamson, M.; Grubb, A.; Brömme, D. Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases. J. Med. Chem.,  2002, 45(19), 4202-4211.
[http://dx.doi.org/10.1021/jm020850k] [PMID:  12213061] 
[75] 
Verhelst, S.H.L.; Witte, M.D.; Arastu-Kapur, S.; Fonovic, M.; Bogyo, M. Novel aza peptide inhibitors and active-site probes of papain-family cysteine proteases. ChemBioChem,  2006, 7(6), 943-950.
[http://dx.doi.org/10.1002/cbic.200600001] [PMID:  16607671] 
[76] 
Ollivier, N.; Besret, S.; Blanpain, A.; Melnyk, O. Silver-catalyzed azaGly ligation. Application to the synthesis of azapeptides and of lipid-peptide conjugates. Bioconjug. Chem.,  2009, 20(7), 1397-1403.
[http://dx.doi.org/10.1021/bc9000195] [PMID:  19522459] 
[77] 
Mhidia, R.; Melnyk, O. Selective cleavage of an azaGly peptide bond by copper(II). Long-range effect of histidine residue. J. Pept. Sci.,  2010, 16(3), 141-147.
[http://dx.doi.org/10.1002/psc.1211] [PMID:  20131312] 
[78] 
Abo-Dya, N.E.; Biswas, S.; Basak, A.; Avan, I.; Alamry, K.A.; Katritzky, A.R. Benzotriazole-mediated synthesis of aza-peptides: En route to an aza-leuenkephalin analogue. J. Org. Chem.,  2013, 78(8), 3541-3552.
[http://dx.doi.org/10.1021/jo302251e] [PMID:  23373789] 
[79] 
Bourguet, C.B.; Sabatino, D.; Lubell, W.D. Benzophenone semicarbazone protection strategy for synthesis of aza-glycine containing aza-peptides. Biopolymers,  2008, 90(6), 824-831.
[http://dx.doi.org/10.1002/bip.21103] [PMID:  18844293] 
[80] 
Liley, M.; Johnson, T. Solid phase synthesis of azapeptides utilising reversible amide bond protection to prevent hydantoin formation. Tetrahedron Lett.,  2000, 41(20), 3983-3985.
[http://dx.doi.org/10.1016/S0040-4039(00)00534-7] 
[81] 
Garcia-Ramos, Y.; Lubell, W.D. Synthesis and alkylation of aza-glycinyl dipeptide building blocks. J. Pept. Sci.,  2013, 19(12), 725-729.
[http://dx.doi.org/10.1002/psc.2572] [PMID:  24203503] 
[82] 
Doan, N-D.; Zhang, J.; Traoré, M.; Kamdem, W.; Lubell, W.D. Solid-phase synthesis of C-terminal azapeptides. J. Pept. Sci.,  2015, 21(5), 387-391.
[http://dx.doi.org/10.1002/psc.2711] [PMID:  25400083] 
[83] 
Ooi, T.; Kameda, M.; Maruoka, K. Molecular design of a C2-symmetric chiral phase-transfer catalyst for practical asymmetric synthesis of α-Amino Acids. J. Am. Chem. Soc.,  1999, 121(27), 6519-6520.
[http://dx.doi.org/10.1021/ja991062w] 
[84] 
Ooi, T.; Tayama, E.; Maruoka, K. Highly stereoselective N-terminal functionalization of small peptides by chiral phase-transfer catalysis. Angew. Chem. Int. Ed.,  2003, 42(5), 579-582.
[http://dx.doi.org/10.1002/anie.200390167] [PMID:  12569496] 
[85] 
Zhao, L.; Li, C-J. Functionalizing glycine derivatives by direct C-C bond formation. Angew. Chem. Int. Ed. Engl.,  2008, 47(37), 7075-7078.
[http://dx.doi.org/10.1002/anie.200801367] [PMID:  18671311] 
[86] 
Zhao, L.; Baslé, O.; Li, C-J. Site-specific C-functionalization of free-(NH) peptides and glycine derivatives via direct C-H bond func-tionalization. Proc. Natl. Acad. Sci. USA,  2009, 106(11), 4106-4111.
[http://dx.doi.org/10.1073/pnas.0809052106] [PMID:  19251635] 
[87] 
Bowles, M.; Proulx, C. Methods in Enzymology; Petersson, E.J., Ed.; Academic Press, 2021, Vol. 656, pp. 169-190.
[88] 
Zhang, J.; Proulx, C.; Tomberg, A.; Lubell, W.D. Multicomponent diversity-oriented synthesis of aza-lysine-peptide mimics. Org. Lett.,  2014, 16(1), 298-301.
[http://dx.doi.org/10.1021/ol403297v] [PMID:  24328523] 
[89] 
Proulx, C.; Lubell, W.D. Copper-catalyzed N-arylation of semicarbazones for the synthesis of aza-arylglycine-containing aza-peptides. Org. Lett.,  2010, 12(13), 2916-2919.
[http://dx.doi.org/10.1021/ol100932m] [PMID:  20536163] 
[90] 
Proulx, C.; Lubell, W.D. Aza-1,2,3-triazole-3-alanine synthesis via copper-catalyzed 1,3-dipolar cycloaddition on aza-progargylglycine. J. Org. Chem.,  2010, 75(15), 5385-5387.
[http://dx.doi.org/10.1021/jo100957z] [PMID:  20583744] 
[91] 
Kato, M.; Abe, M.; Kuroda, Y.; Hirose, M.; Nakano, M.; Handa, T. Synthetic pentapeptides inhibiting autophosphorylation of insulin receptor in a non-ATP-competitive mechanism. J. Pept. Sci.,  2009, 15(5), 327-336.
[http://dx.doi.org/10.1002/psc.1114] [PMID:  19206072] 
[92] 
Diamond, B.; Volpe, B.T.; VanPatten, S.; Al Abed, Y. SARS-CoV-2 and interferon blockade. Mol. Med.,  2020, 26(1), 103.
[http://dx.doi.org/10.1186/s10020-020-00231-w] [PMID:  33167852] 
[93] 
Dai, C.; Ma, J.; Li, M.; Wu, W.; Xia, X.; Zhang, J. Diversity-oriented submonomer synthesis of azapeptides mediated by the Mitsunobu reaction. Org. Chem. Front.,  2019, 6(14), 2529-2533.
[http://dx.doi.org/10.1039/C9QO00296K] 
[94] 
Torrini, I.; Zecchini, G.P. Paglialunga; Paradisi, M.; Mastropietro, G.; Lucente, G.; Gavuzzo, E.; Mazza, F. Topographically con-strained aromatic α-aza-amino acids. Part 2. New azaTic-containing peptides: Synthesis, conformation, and intramolecular NH…N inter-action. Tetrahedron,  1999, 55(7), 2077-2090.
[http://dx.doi.org/10.1016/S0040-4020(98)01219-8] 
[95] 
Melton, S.D.; Smith, M.S.; Chenoweth, D.M. Incorporation of aza-glycine into collagen peptides. J. Org. Chem.,  2020, 85(3), 1706-1711.
[http://dx.doi.org/10.1021/acs.joc.9b02539] [PMID:  31724856] 
[96] 
Grzyb, J.A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R.S.; Batey, R.A. Carbamoylimidazolium and thiocarbamoylimidazolium salts: Novel reagents for the synthesis of ureas, thioureas, carbamates, thiocarbamates and amides. Tetrahedron,  2005, 61(30), 7153-7175.
[http://dx.doi.org/10.1016/j.tet.2005.05.056] 
[97] 
Hansen, T.K. Synthesis of azapeptides from hindered amines leading to novel growth hormone secretagogues. Tetrahedron Lett.,  1999, 40(51), 9119-9120.
[http://dx.doi.org/10.1016/S0040-4039(99)01888-2] 
[98] 
Al-Abed, Y.; Cheng, K.F. Preparation of O-benzotriazole
and O-imidazole synthons for use in the synthesis of peptidomimetics
including azapeptides. Patent
WO2020227594 2020.
[99] 
Al-Abed, Y.; Altiti, A. Preparation of acyl thiols including
thiosemicarbazates and their use in the synthesis of peptides
and peptidomiometics. Patent WO2020227592 2020.
[100] 
Al-Abed, Y.; Altiti, A. Preparation of dimers including acyl
thiocarbazates for use in synthesis of peptidomimetics. Patent
WO2021226431, 2021.
Cite As
Current Medicinal Chemistry

Azapeptides -A History of Synthetic Milestones and Key Examples

Abstract
