Edited by Andrew B Hughes Amino Acids, Peptides and Proteins in Organic Chemistry Further Reading Pignataro, B (ed.) Drauz, K., Gröger, H., May, O (eds.) Ideas in Chemistry and Molecular Sciences Enzyme Catalysis in Organic Synthesis Advances in Synthetic Chemistry Third, completely revised and enlarged edition 2010 ISBN: 978-3-527-32539-9 Volumes 2011 Theophil Eicher, Siegfried Hauptmann and Andreas Speicher ISBN: 978-3-527-32547-4 The Chemistry of Heterocycles Fessner, W.-D., Anthonsen, T Structure, Reactions, Synthesis, and Applications Modern Biocatalysis 2011 Stereoselective and Environmentally Friendly Reactions ISBN: 978-3-527-32868-0 (Hardcover) ISBN: 978-3-527-32747-8 (Softcover) 2009 Royer, J (ed.) Lutz, S., Bornscheuer, U T (eds.) Asymmetric Synthesis of Nitrogen Heterocycles Protein Engineering Handbook 2009 2009 ISBN: 978-3-527-32036-3 ISBN: 978-3-527-31850-6 Reek, J N H., Otto, S Sewald, N., Jakubke, H.-D Dynamic Combinatorial Chemistry Peptides: Chemistry and Biology 2010 2009 ISBN: 978-3-527-32122-3 ISBN: 978-3-527-31867-4 Rutjes, F., Fokin, V V (eds.) Jakubke, H.-D., Sewald, N Click Chemistry Peptides from A to Z in Chemistry, Biology and Macromolecular Science A Concise Encyclopedia 2011 ISBN: 978-3-527-31722-6 ISBN: 978-3-527-32071-4 Volume Set 2008 ISBN: 978-3-527-32085-1 Nicolaou, K C., Chen, J S Classics in Total Synthesis III New Targets, Strategies, Methods 2011 ISBN: 978-3-527-32958-8 (Hardcover) ISBN: 978-3-527-32957-1 (Softcover) Edited by Andrew B Hughes Amino Acids, Peptides and Proteins in Organic Chemistry Volume - Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis The Editor Andrew B Hughes La Trobe University Department of Chemistry Victoria 3086 Australia All books published by Wiley-VCH are carefully produced Nevertheless, authors, editors, and publisher not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de # 2011 WILEY-VCH Verlag & Co KGaA, Boschstr 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Composition Thomson Digital, Noida, India Printing and Bookbinding Strauss GmbH, Mörlenbach Cover Design Schulz Grafik Design, Fußgönheim Printed in the Federal Republic of Germany Printed on acid-free paper ISBN: 978-3-527-32103-2 V Contents List of Contributors 1.1 1.2 1.2.1 1.2.1.1 1.2.1.1.1 1.2.1.1.2 1.2.1.1.3 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.4.1 1.2.1.4.2 1.2.1.4.3 1.2.1.4.4 1.2.1.5 1.2.2 1.2.2.1 1.2.2.2 1.2.2.2.1 1.2.2.2.2 1.2.2.2.3 1.2.2.2.4 1.2.2.3 1.2.2.4 1.2.2.4.1 1.2.2.4.2 1.2.2.5 XVII Protection Reactions Vommina V Sureshbabu and Narasimhamurthy Narendra General Considerations a-Amino Protection (Na Protection) Non-Urethanes Acyl Type Monoacyl Groups Groups Cleavable via Lactam Formation Diacyl Groups Phosphine-Type Groups 10 Sulfonyl-Type Groups 10 Alkyl-Type Groups 11 Triphenylmethyl (Trityl or Trt) Group 11 Benzhydryl Groups 12 N,N-Bis-Benzyl Protection 12 Vinyl Groups 12 Sulfanyl-Type Groups 13 Urethanes (Carbamates or Alkyloxycarbonyl Groups) 14 Formation of the Urethane Bond 16 Urethanes Derived from Primary Alcohols 16 Benzyloxycarbonyl (Cbz or Z) Group 16 Urethanes Cleaved by b-Elimination 19 Urethanes Cleaved via Michael-Type Addition 24 Allyloxycarbonyl (Aloc) Group 25 Urethane Groups Derived from Secondary Alcohols 25 Urethanes Derived from Tertiary Alcohols 25 tert-Butoxycarbonyl (Boc) Group 25 Boc Analogs 28 Other Aspects of Urethane Protectors 29 Amino Acids, Peptides and Proteins in Organic Chemistry Vol.4 – Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis Edited by Andrew B Hughes Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32103-2 VI Contents 1.2.2.5.1 1.2.2.5.2 1.2.2.5.3 1.2.2.5.4 1.2.3 1.2.3.1 1.2.3.2 1.2.3.3 1.3 1.3.1 1.3.1.1 1.3.2 1.3.2.1 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.4 1.4.1 1.4.2 1.4.2.1 1.4.2.2 1.4.2.3 1.4.3 1.4.4 1.4.5 1.4.6 1.4.6.1 1.4.6.1.1 1.4.6.1.2 1.4.6.1.3 1.4.6.2 1.4.7 1.4.8 1.4.9 1.4.9.1 1.5 1.6 1.7 1.7.1 1.7.1.1 Formation of Dipeptide Impurities during the Introduction of Urethanes and Protocols to Overcome It 29 Introduction of Urethanes via Transprotection 30 Protection of the Nitrogen of a-Amino Acid N-Carboxy Anhydrides (NCAs) 31 Na,Na-bis-Protected Amino Acids 32 Other Na-Protecting Groups 32 a-Azido Acids as a-Amino Acid Precursors 33 One-Pot Na Protection and Ca Activation 33 Effect of Na-Protecting Groups in the Synthesis of NMAs 33 Carboxy Protection 34 Methyl and Ethyl Esters 35 Substituted Methyl and Ethyl Esters 36 Benzyl Ester 36 Cleavage 36 Substituted Benzyl Esters 38 tert-Butyl Ester 38 Other Acid-Labile Esters 39 Temporary a-Carboxy Protection 39 a-Carboxy Protectors as Precursors to Useful Amino Acid Derivatives: Formation of Acid Hydrazides 41 Side-Chain Protection 41 o-Amino Group of Diamino Acids 41 Guanidino Group of Arg 43 Protection Through Protonation 43 Nitration 44 Arg Precursors 45 Imidazole Group of His 45 Indole Group of Trp 48 o-Amido Group of Asn and Gln 49 b-Thiol Group of Cys 50 Common Side-Reactions with S-Protected Cys Derivatives 51 Racemization 51 b-Elimination 51 Oxidation 51 Synthesis of Peptides Using Cystine as ‘‘Self-Protected’’ Cys 51 Thioether Group of Met 53 Hydroxy Group of Ser, Thr, and the Phenolic Group of Tyr 54 o-Carboxy Group of Asp and Glu 55 Aspartimide Formation 55 Photocleavable Protections 57 Conclusions 58 Experimental Procedures 59 Protection Reactions 59 General Procedure for the Preparation of Tfa-Arg-OH 59 Contents 1.7.1.2 1.7.1.3 1.7.1.4 1.7.1.5 1.7.1.5.1 1.7.1.5.2 1.7.1.6 1.7.1.6.1 1.7.1.6.2 1.7.1.6.3 1.7.1.6.4 1.7.1.7 1.7.1.8 1.7.1.9 1.7.1.10 1.7.1.10.1 1.7.1.10.2 1.7.1.10.3 1.7.1.11 1.7.1.12 1.7.1.13 1.7.1.13.1 1.7.1.13.2 1.7.1.13.3 1.7.1.13.4 1.7.1.14 1.7.1.15 1.7.1.15.1 1.7.1.16 1.7.1.16.1 1.7.1.17 General Procedure for the Preparation of Na-Phthaloyl Amino Acids using N-(Ethoxycarbonyl)phthalimide 59 General Procedure for the Preparation of Na-Trt-Amino Acids 59 General Procedure for the Preparation of Na-Ns-Amino Acids 60 General Procedure for the Preparation of Na-Z-Amino Acids 61 Method A: Using Z-Cl 61 Method B: Using Z-OSu 62 General Procedures for the Preparation of Na-Fmoc-Amino Acids 62 Method A: Using Fmoc-OSu 62 Method B: Using Fmoc-Cl and N,O-bis-TMS-Amino Acids 62 Method C: Using Fmoc-Cl in the Presence of Zinc Dust 63 Method D: Using Fmoc-N3 63 General Procedure for the Preparation of Na-Nsc-Amino Acids 64 General Procedure for the Preparation of Na-Bsmoc-Amino Acids 64 General Procedure for the Preparation of Na-Aloc-Amino Acids 65 General Procedures for the Preparation of Na-Boc-Amino Acids 65 Method A: Using (Boc)2O 65 Method B: Using Boc-ON 65 Method C: Using Boc-N3 66 General Procedure for the Preparation of N,N0 -di-Boc-Amino Acids 66 General Procedure for the Preparation of Na-Bpoc-Amino Acids 67 General Procedures for the Preparation of Amino Acid Methyl Esters 68 Preparation of Amino Acid Methyl Ester Hydrochloride Salts 68 Isolation of Amino Acid Methyl Esters: Deprotonation of the Hydrochloride Salt Using Zinc Dust 69 Glutamic Acid a-Methyl, c-tert-Butyl Diester Using Diazomethane 69 Z-Glu-OMe via Methanolysis of Cyclic Anhydride 69 General Procedure for the Preparation of Amino Acid Ethyl Esters 69 General Procedure for the Preparation of Amino Acid Benzyl Ester p-Toluenesulfonate Salts 70 Preparation of Amino Acid Benzyl Ester p-Toluenesulfonate Salts Under Microwave Irradiation 70 General Procedure for the Preparation of tert-Butyl Esters of Na-Unprotected Amino Acids Using Isobutene 71 Preparation of Z-Phe-OtBu by the Silver Salt Method 71 General Procedure for Concomitant Protection and Activation of Amino Acids Using Pentafluorophenyl Carbonate 80 VII VIII Contents 1.7.2 1.7.2.1 1.7.2.2 1.7.2.3 1.7.2.3.1 1.7.2.3.2 1.7.2.3.3 1.7.2.4 1.7.2.4.1 1.7.2.4.2 1.7.2.5 1.7.2.5.1 1.7.2.5.2 1.7.2.6 1.7.2.7 1.7.2.8 1.7.2.9 1.7.2.10 1.7.2.11 1.7.2.12 1.7.2.13 Deprotection Reactions 81 Removal of the Phth Group by Hydrazinolysis 81 Removal of the Nps Group 81 Removal the Z-group 82 Protocol A: Employing CH 82 Protocol B: Employing Silylhydride 82 Protocol C: Through CTH using 1,4-Cyclohexadieneas Hydrogen Donor 83 Cleavage of the Fmoc Group 83 Method A: Using TAEA [67] 83 Method B: Using DEA: Simultaneous Removal of the Fmoc Group and 9-Fluorenylmethyl Ester 83 Cleavage of the Boc Group 84 Protocol A: Removal of the Boc group with TFA in the Presence of Scavengers 84 Protocol B: Cleavage of Boc Group with TMS/Phenol 84 Transprotection of Na-Protecting Groups: Fmoc-Met-OH to Boc-Met-OH 84 Selective Methyl Ester Hydrolysis in the Presence of the Na-Fmoc Group 84 Cleavage of tert-Butyl Ester Using BF3ÁEt2O 84 Selective Cleavage of Phenacyl Ester in the Presence of the Na-Nosyl Group 85 Removal of the Trt Group (Iodolysis) 85 Deprotection of the Pbf Group from Z-Arg(Pbf)-OH 85 Removal of the Phenoc Group through Photolysis 85 Conversion of the DCHA Salt of Na-Protected Amino Acids into Free Acids 85 References 86 Part One Amino Acid-Based Peptidomimetics 2.1 2.2 2.3 2.4 2.5 2.6 2.7 99 Huisgen Cycloaddition in Peptidomimetic Chemistry 101 Daniel Sejer Pedersen and Andrew David Abell Introduction 101 Huisgen [2 þ 3] Cycloaddition Between Azides and Acetylenes 102 Mechanistic Consideration for the Cu-Huisgen and Ru-Huisgen Cycloadditions 103 Building Blocks for the Synthesis of Triazole-Modified Peptidomimetics 106 Cyclic Triazole Peptidomimetics 109 Acyclic Triazole Peptidomimetics 113 Useful Experimental Procedures 121 Contents 2.7.1 2.7.2 2.7.3 3.1 3.1.1 3.1.2 3.1.3 3.1.4 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 Monitoring Huisgen Cycloadditions and Characterizing Triazoles 121 General Procedure for the Synthesis of 1,4-Triazoles Using Cu-Huisgen Cycloaddition 122 General Procedure for the Synthesis of 1,5-Triazoles Using Ru-Huisgen Cycloaddition 123 References 124 Recent Advances in b-Strand Mimetics 129 Wendy A Loughlin and David P Fairlie Introduction 129 b-Strands 129 b-Sheets 130 Differences in Strand/Sheet/Turn/Helix Recognition 130 Towards b-Strand Mimetics 131 Macrocyclic Peptidomimetics 133 Acyclic Compounds 135 Aliphatic and Aromatic Carbocycles 136 Ligands Containing One Ring with One Heteroatom (N) 137 Ligands Containing One or Multiple Rings with One Heteroatom (O, S) 138 Ligands Containing One Ring with Two Heteroatoms (N,N) 139 Ligands Containing One Ring with Two Heteroatoms (N,S) or Three Heteroatoms (N,N,S or N,N,N) 140 Ligands Containing Two Rings with One Heteroatom (N or O) 140 Ligands Containing Two Rings with Two or Three Heteroatoms (N,N or N,S or N,N,N) 141 Conclusions 142 References 143 Part Two Medicinal Chemistry of Amino Acids 149 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.3.4 4.4 4.4.1 4.4.2 4.5 Medicinal Chemistry of a-Amino Acids 151 Lennart Bunch and Povl Krogsgaard-Larsen Introduction 151 Glutamic Acid 151 Conformational Restriction 153 Synthesis – General Considerations 154 Case Study: Synthesis of DCAN 155 Case Study: Synthesis of LY354740 157 Case Study: Synthesis of ABHD-V and ABHD-VI 158 Bioisosterism 159 Case Study: Design and Synthesis of AMPA 160 Case Study: Design and Synthesis of Thioibotenic Acid Structure–Activity Studies 162 161 IX j 15 Amino Acid-Based Dendrimers 516 65 Kofoed, J and Reymond, J.-L (2005) 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 Current Opinion in Chemical Biology, 9, 656–664 Darbre, T and Reymond, J.-L (2006) Accounts of Chemical Research, 39, 925–934 Delort, E., Darbre, T., and Reymond, J.-L (2004) Journal of the American Chemical Society, 126, 15642–15643 Delort, E., Nguyen-Trung, N.-Q., Darbre, T., and Reymond, J.-L (2006) The Journal of Organic Chemistry, 71, 4468–4480 Maillard, N., Clouet, A., Darbre, T., and Reymond, J.-L (2009) Nature Protocols, 4, 132–142 Sommer, P., Uhlich, N.A., Reymond, J.L., and Darbre, T (2008) ChemBioChem, 9, 689–693 Trinchi, A and Muster, T.H (2007) Supramolecular Chemistry, 19, 431–445 Balzani, V., Ceroni, P., Gestermann, S., Gorka, M., Kauffmann, C., and V€ogtle, F (2000) Journal of the Chemical Society, Dalton Transactions, 3765–3771 Vicinelli, V., Ceroni, P., Maestri, M., Balzani, V., Gorka, M., and V€ogtle, F (2002) Journal of the American Chemical Society, 124, 6461–6468 Reynolds, C.H., Annan, N., Beshah, K., Huber, J.H., Shaber, S.H., Lenkinski, R.E., and Wortman, J.A (2000) Journal of the American Chemical Society, 122, 8940–8945 Nicolle, G.M., Toth, E., Schmitt-Willich, H., Rad€ uchel, B., and Merbach, A.E (2002) Chemistry – A European Journal, 8, 1040–1048 Dirksen, A., Meijer, E.W., Adriaens, W., and Hackeng, T.M (2006) Chemical Communications, 1667–1669 Fischer, P.M (2007) Medicinal Research Reviews, 27, 755–795 Parekh, H.S (2007) Current Pharmaceutical Design, 13, 2837–2850 Foged, C and Nielsen, H.M (2008) Expert Opinion on Drug Delivery, 5, 105–117 Veldhoen, S., Laufer, S.D., and Restle, T (2008) International Journal of Molecular Sciences, 9, 1276–1320 Paleos, C.M., Tziveleka, L.-A., Sideratou, Z., and Tsiourvas, D (2009) Expert Opinion on Drug Delivery, 6, 27–38 82 Ramaswamy, C., Sakthivel, T., 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 Wilderspin, A.F., and Florence, A.T (2003) The International Journal of Pharmaceutics, 254, 17–21 Tung, C.-H., Mueller, S., and Weissleder, R (2002) Bioorganic and Medicinal Chemistry, 10, 3609–3614 Coles, D.J., Yang, S., Esposito, A., Mitchell, D., Minchin, R.F., and Toth, I (2007) Tetrahedron, 63, 12207–12214 Yang, S., Coles, D.J., Esposito, A., Mitchell, D.J., Toth, I., and Minchin, R.F (2009) Journal of Controlled Release, 135, 159–165 Al-Jamal, K.T., Ramaswamy, C., and Florence, A.T (2005) Advanced Drug Delivery Reviews, 57, 2238–2270 Bayele, H.K., Sakthivel, T., O’Donell, M., Pasi, K.J., Wilderspin, A.F., Lee, C.A., Toth, I., and Florence, A.T (2005) Journal of Pharmaceutical Sciences, 94, 446–457 Chen, Q.-R., Zhang, L., Stass, S.A., and Mixson, A.J (2001) Nucleic Acids Research, 29, 1334–1340 Leng, Q.X and Mixson, A.J (2005) Nucleic Acids Research, 33, e40/1–e40/90 Leng, Q., Scaria, P., Zhu, J.S., Ambulos, N., Campbell, P., and Mixson, A.J (2005) The Journal of Gene Medicine, 7, 977–986 Leng, Q.X and Mixson, A.J (2005) Cancer Gene Therapy, 12, 682–690 Leng, Q., Scaria, P., Ioffe, O.B., Woodle, M., and Mixson, A.J (2006) The Journal of Gene Medicine, 8, 1407–1415 Leng, Q., Scaria, P., Lu, P., Woodle, M.C., and Mixson, A.J (2008) Cancer Gene Therapy, 15, 485–495 Yan, Z., Zou, H., Tian, F., Grandis, J.R., Mixson, A.J., Lu, P.Y., and Li, L.-Y (2008) Molecular Cancer Therapeutics, 7, 1355–1364 Fassina, G (1992) Journal of Chromatography A, 591, 99–106 Wathier, M., Jung, P.J., Carnahan, M.A., Kim, T., and Grinstaff, M.W (2004) Journal of the American Chemical Society, 126, 12744–12745 Wathier, M., Johnson, C.S., Kim, T., and Grinstaff, M.W (2006) Bioconjugate Chemistry, 17, 873–876 Wathier, M., Johnson, M.S., Carnahan, M.A., Baer, C., McCuen, B.W., Kim, T., References and Grinstaff, M.W (2006) ChemMedChem, 1, 821–825 99 Cloninger, M.J (2002) Current Opinion in Chemical Biology, 6, 742–748 100 Lee, C.C., MacKay, J.A., Frechet, J.M.J., and Szoka, F.C (2005) Nature Biotechnology, 23, 1517–1526 101 Niederhafner, P., Reinis, M., Sebestik, J., and Jezek, J (2008) Journal of Peptide Science, 14, 556–587 102 Niederhafner, P., Sebestik, J., and Jezek, J (2008) Journal of Peptide Science, 14, 2–43 103 Niederhafner, P., Sebestik, J., and Jezek, J (2008) Journal of Peptide Science, 14, 44–65 j517 j519 Index a Acacia willardiana 160 N-acetyl galactosamine (GalNAc) 321, 359 acid-labile alkyl esters 39 acid-mediated formation of pGlu 50 acidolysis 35 actinomycin D (DactinomycinÒ ) 259, 260 acyclic compounds 135, 136 acyclic triazole peptidomimetics 113–121 – cis-amide bond peptidomimetics 120 – conditions for 120 – exchange of dipeptide fragment with 115 – peptidomimetic inhibitors of HIV-1 protease 114 – regioselective, sequential Cu-Huisgen synthesis of pseudo-nonapeptidomimetics 118 – solid-phase Cu-Huisgen backbone and sidechain cycloaddition 114 – solution-phase synthesis of triazole trimer 116 – synthesis of – 1,4-and 1,5-triazole dipeptide replacements in native protein 119 – b-turn-inducing 1,4-triazole peptidomimetics 115 alicyclic b-amino acids – five-membered alicyclic b-amino acids 175–179 – – amipurimycin 176 – – antifungal activity 177 – – cispentacin 176 – – structure–activity relationship 178 – – synthesis 179 – – in vitro activity 180–182 – medicinal chemistry 175 – six-membered alicyclic b-amino acids 179–186 – – structure–activity relationship 185 – – synthesis of tilidine 184 – – tachykinin NK1 receptor antagonists 185 4-alkylGlu analogs, binding affinities 165 4-alkylidene Glu analogs, binding affinities 166, 167 allophenylnorstatine (Apns) 214 Alzheimer’s disease 220 Amanita muscaria 160 Amanita pantherina 160 Amanita strobiliformis 160 amastatin 209 o-amido group of Asn and Gln 49 – acid-mediated formation of pGlu 50 – o-amide protections (selected examples) 50 – nitrile and aspartimide from unprotected Asn 49 Z-amino acid azides, from methyl esters 41 amino acid-based dendrimers – peptide dendrimers applications – – as antimicrobial agents 502–504 – – as DNA/RNA delivery vectors 507–512 – – initial efforts on MAPs 502 – – ion sensors and MRi contrast agents 505–507 – – as protein/enzyme mimics 504, 505 – peptide dendrimer synthesis 491–502 – – glutamic/aspartic acid, proline, and arginine dendrimers 494–497 – – grafted on PAMAM 500–502 – – MAPs synthesis 497–500 – – polylysine dendrimers synthesis 493 amino acids 135, 247 Amino Acids, Peptides and Proteins in Organic Chemistry Vol.4 – Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis Edited by Andrew B Hughes Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32103-2 j Index 520 – side-chain functional groups, entail protection a-amino acids 151 – bioisosterism 159–162 – – AMPA, design and synthesis 160, 161 – – thioibotenic acid, design and synthesis 161, 162 – conformational restriction 153–159 – – ABHD-V and ABHD-VI 159 – – DCAN synthesis 156–158 – – LY354740 synthesis 158 – glutamic acid 151–153 – structure–activity studies 162–168 – – AMPA analogs 162, 163 – – 4-substituted Glu analogs 163–168 aminoacyl-tRNA synthetases 386 (2S,4R)-2-amino-4-(3-(2,2diphenylethylamine)-3-oxopropyl) pentanedioic acid (DPAG) 168 3-amino-2-hydroxydecanoic acid (AHDA) 190, 204, 213 (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6Hcyclohepta [d] isoxazol-4-yl)propionic acid (4AHCP) 163 3-amino-2-hydroxymethylhexanoic acid (AHMHA) 197, 202, 210 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) receptors 151 – analogs 162, 163 – binding affinities 154, 163 – chemical structures of 163 – design and synthesis 160, 161 3-amino-2-hydroxyphenylbutanoic acid (AHPA) 197, 199, 200, 210 (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4isoxazolyl)propionic acid (ATPA) 163 – functional characterization of 164 3-amino-2-oxopropanoate 192 aminopeptidase P (AP-P) 210 – AP-P inhibitors 210 aminopeptidases, inhibitors of 207–211 a-amino protection – non-urethanes – – acyl type 4, – – alkyl-type groups 11 – – benzhydryl groups 12 – – diacyl groups – – groups cleavable via lactam formation – – groups removed by reductive cleavage 8, – – monoacyl groups – – N,N-bis-benzyl protection 12 – – phosphine-type groups 10 – – phthaloyl (Phth) group 7, – – sulfanyl-type groups 13, 14 – – sulfonyl-type groups 10, 11 – – trifluoroacetyl (Tfa) group 5, – – triphenylmethyl (Trityl or Trt) group 11, 12 – – vinyl groups 12, 13 – urethanes (carbamates/alkyloxycarbonyl groups) 14, 15 – – allyloxycarbonyl (Aloc) group 25 – – benzyloxycarbonyl (Cbz or Z) group 15–19 – – bond, formation of 15 – – tert-butoxycarbonyl (Boc) group 25–29 – – cleaved by b-elimination 19 – – cleaved via Michael-type addition 24 – – derived from primary alcohols 15 – – derived from tertiary alcohols 25 – – 9-fluorenylmethoxycarbonyl (Fmoc) group 19–23 – – groups derived from secondary alcohols 25 – – sulfonylethoxycarbonyl groups 23, 24 amipurimycin 176 angiotensin-converting enzyme (ACE) 212 – inhibitors 215 antibacterial agents 205–207 antifreeze glycopeptides (AFGPs) 375 antihyperglycemics – exendin-4 (see Exenatide (ByettaÒ )) – liraglutide 255 – symlin (pramlintide) 254 antimicrobial peptides 263–267 – daptomycin 266 – gramicidin S 267 – polymyxin 265, 266 apstatin 209, 210 arginine dendrimer, structures 497 aspartyl proteases inhibitors 211, 212 – BACE-1 inhibitors 224–227 – catalytic mechanism 212 – HIV-1 protease inhibitors 216–220 – HTLV-I inhibitors 220, 221 – plasmepsin II inhibitors 222–224 – renin inhibitors 212–216 asymmetric epoxidation 191 (Æ)-2-azanorbornane-3-exo,5-endo-dicarboxylic acid (DCAN) 153 – in silico studies 154 – synthesis 156–158 azide–alkyne cycloaddition 372 a-azido acids, as a-amino acid precursors 33 azido alanine 108 aziridine-containing peptides 361 azlactones Index b BACE-1 inhibitors 224–227 – design and structures 225 Bacillus lentis 368 benzyl esters 36, 38 bestatin 205, 207, 208 – interactions in active site of MAPs 209 – synthesis 208 Bestmann–Ohira reagent 107 bicyclooctane-2-aza-dicarboxylate (BOAD) 153 bioisosterism 159–162 – case studies – – AMPA, design and synthesis 160, 161 – – thioibotenic acid, design and synthesis 161, 162 – naturally occurring Glu analogs containing 160 Biopharmaceutics Classification System (BCS) 278 N,N-bis-benzyl amino acids 12 blood coagulation inhibitors – bivalirudin 251 – integrilin (eptifibatide) 251 N-Boc-protected prolinol 120 N-Boc-(2S,3S)-3-amino-2-hydroxy-5phenylpentanoic acid (AHPPA) 202 bortezomib (VelcadeÒ ) 259 bovine serum albumin (BSA) 331 bradykinin 255 branched peptides – as antimicrobials 270 – solid-phase synthesis of 267 – as tumor-targeting agents 268–270 N-bromosuccinimide 33 Brønsted bases 310 Burgess reagent tert-butyldimethylsilyl (TBS) 346 tert-butyl esters 38, 39 c calcitonin 256 calmodulin 459 Campylobacter jejuni 386 cancer chemotherapy 258 Candida cylindracea lipases (CCL) 192 carbamate-tethered glycosides 362 carbocycles, aliphatic and aromatic 136, 137 N-carboxy anhydrides, protection of 31 o-carboxy group protection, of asp and glu 55 – aspartimide formation 55–57 – o-esters of asp and glu (selected examples) 59 carboxymethylcyclodextran 232 carboxy protections 3, 28, 34, 35, 39, 40, 55, 57 – acid-labile esters 39 – benzyl ester 36 – – tert-butyl ester 38, 39 – – cleavage 36 – – substituted benzyl esters 38 – – substituted methyl and ethyl esters 37, 38 – a-carboxy protectors as precursors to 41 – methyl and ethyl esters 35, 36 – selected carboxy protections 40 – substituted methyl and ethyl esters 36 – temporary a-carboxy protection 39, 41 cell-based receptor activation assays 284 central nervous system (CNS) 151 cerium ammonium nitrate (CAN) 346 chiral acylchloride strategy 306 m-chloroperbenzoic acid (mCPBA) 11 chymotrypsin 214 circular dichroism (CD) 114 cispentacin – antifungal activity 175, 177 – structure 176 – structure–activity relationship 176 – in vitro activity 180–183 cleavage – of APP by BACE 224 – conditions for (see carboxy protections; o-amide protections) – by different peptidases 269 – of ester linker 430 – of Fmoc group 83 – groups removed by reductive – Leu–Pro cleavage site 220 – mechanism of Na-Bsmoc cleavage 24 – Na-Dim group, by bromination 13 – Na-Nps group 14 – Na-Phth group – Na protection via lactam formation – of peptide resins 423 – of peptides from solid support 400 – by proteases 409 – selective, phenacyl ester in presence of 85 – of tBu-ester 326 – with TFA 343 – thiolytic cleavage of Na-Dts protection – for urethane protections 16 – – cleaved by b-elimination 19 coagulation disorders 251 CODESÔ technology 287 colistin 265 combinatorial chemistry 395 computational design, of proteins 473 confocal microscopy 414 conformational restriction 153–155 j521 j Index 522 – case studies – – synthesis of ABHD-V and ABHD-VI 159 – – synthesis of DCAN 156–158 – – synthesis of LY354740 158 – conformationally restricted Glu analogs 155 – mechanism of iGluR activation 156 coumarin derivatives 233 cross-metathesis 378 – protein modification by transition metals 379 – sulfur-assisted 380 – synthesis of neoglycosides via 380 CuAAC see Cu(I)-catalyzed azide-alkyne click cycloaddition (CuAAC) Cu-Huisgen cycloaddition reaction 103 – applications 103 – mechanism for 104 – mechanistic consideration for 103–106 – pseudo-nona-peptidomimetics, regioselective, sequential synthesis 118 Cu(I)-catalyzed azide–alkyne click cycloaddition (CuAAC) 372 – applications 373 – – Danishefsky’s glycosyl amino acid syntheses 382 – – pentavalent vaccine construct 383 – – synthetic vaccine against small-cell lung cancer 384 – – vaccine constructs synthesis 381 – azide–alkyne cycloaddition 372 – 1,4-disubstituted triazoles as peptide isosteres 373 – and neoglycoproteins 376–378 – neoglycoside and neoglycopeptide synthesis via 373–376 Curtius rearrangement 176 cyclic triazole peptidomimetics 109–113 – cyclization by Cu-Huisgen cycloaddition, lactamization fail to 113 – monocyclization vs cyclodimerization 109 – self-assembling backbone modified peptidomimetics 112 – substitution of trans-amide bond in 112 – VEGFR1 antagonists, synthesis by Cu-Huisgen on-resin cycloaddition 111 cyclodimerization 109–111 cyclohexylnorstatine 203, 204, 214 cyclonorstatine 214 cyclooctadiene (COD) ligand 105 cyclosporine 22, 24, 257 cysteine side-chain modifications 366 – alkylation 367 d dehydroalanine (Dha) 361, 368 dendrimers see peptide dendrimers 6-deoxy-6-aminohexoses 385 deprotection reactions 81 – cleavage of – – Boc group with TMS/phenol 84 – – tert-butyl ester using BF3ÁEt2O 84, 85 – – Fmoc group 83 – – phenacyl ester in presence of Na-nosyl group 85 – conversion of DCHA salt of Na-protected amino acids into 85, 86 – deprotection of Pbf group from Z-Arg(Pbf)OH 85 – removal of – – Boc group with TFA 84 – – Nps group 81, 82 – – phenoc group through photolysis 85 – – phth group by hydrazinolysis 81 – – Trt group 85 – – Z group 82, 83 – selective methyl ester hydrolysis 84 – transprotection of Na-protecting groups: Fmoc-Met-OH to Boc-Met-OH 84 designing modular proteins 474 desmopressin 251 diaminopropionic acid (Dap) 504 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) 112 diazacyclohexanones 139 dichloromethane (DCM) 5, 104 dicyclohexylamine (DCHA) salt 201 dicyclohexylcarbodiimide (DCC) 197, 406 2’,3’-dideoxykanamycin A 207 Diels–Alder reaction 370 diethylenetriaminepentaacetic acid (DTPA) 506 Digenea simplex 152 N,N’-diisopropylcarbodiimide (DIC) 399 diisopropylethylamine (DIPEA) 9, 104, 343 4,5,dimethoxy-2-nitrobenzyloxycarbonyl (Nvoc) 57 2-(3,5-dimethoxyphenyl)prop-2-yloxycarbonyl (Ddz) 57 N,N-dimethylformamide (DMF) 8, 104 3,5-dimethylpyrazole 197 dimethyl (methylthio)sulfonium triflate (DMTST) 340 dimethylsulfoxide (DMSO) 104 dipeptide – formation 30 – impurities 29 – synthesis Index diphenylmethanimine disubstituted Fc–peptide dendrimers, structures 496 DNA polymerase 455 docetaxel 228 drug discovery 101 Dysidea herbacea 153 e edeines 205, 206 electroporation 455 enfuvirtide see fuzeon erythropoietin (EPO) 346 Escherichia coli 210, 376 estrogen receptor b (ER-b) 341 – synthesis 341 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) 370 ethyl esters 35, 36 Evans–Sjögren ketenes 305, 308, 309 excitatory amino acid transporters (EAATs) 152 exenatide (ByettaÒ ) 254, 255 experimental procedures – monitoring and characterizing triazoles 121, 122 – for 1,4-triazoles synthesis using Cu-Huisgen cycloaddition 122, 123 – for 1,4-triazoles synthesis using Ru-Huisgen cycloaddition 123 f factor IXa 184 factor Xa inhibitors 183 9-fluorenylmethylpentafluorophenylcarboante (Fmoc-OPfp) 33 Fmoc donors 30 Fmoc-2-mercaptobenzothiazole (MBT) 30 formulation technologies – absorption enhancers 284, 285 – coadministration with protease inhibitors 285 – formulation vehicles 285, 286 – site-specific delivery 286, 287 fucosyl-peptide dendrimers 503 furin 465 fuzeon 257 g gadomer structure and computer generated model 507 gene/dendrimer cargo, internalization pathway 509 Gibbs free energy equation 153 b-glucosidase 459 glutamatergic neurotransmitter system – malfunctioning 152 – receptor and transporter subtypes in 152 glutamic acid 151–153 – dendrimers synthesis 494, 495 – low-energy conformations 155 glutathione disulfide 345 glycoconjugation 364 glycopeptide 360 see also N-glycopeptides; Oglycopeptides – strategies for synthesis 361 N-glycopeptides synthesis 342–353 – erythropoietin N-glycopeptide fragment 1–28 – – biantennary dodecasaccharide synthesis 346–348 – – reagents and conditions 347, 348 – HIV GP120 V3 domain N-glycopeptide, chemoenzymatic synthesis – – Fmoc-GlcNAc-Asn amino acid building block synthesis 351 – – oxazoline tetrasaccharide donor synthesis 350, 351 – – V3 cyclic GlcNAc peptide and endo A coupling with 352, 353 – N-glycopeptide fragment 1–28 348, 350 – – reagents and conditions 349 – RNase C glycoprotein synthesis 343–345 O-glycopeptides synthesis 324–341 – estrogen receptor peptides synthesis, conformational analysis 340, 341 – Fmoc-GlcNAc-Ser/Thr amino acids synthesis 340 – mucin-type glycopeptides synthesis – – glycopeptide recognition domain, synthesis of 331–339 – – glycopeptide vaccines, synthesis 325–331 – – tumor-associated glycopeptides, synthesis 325–331 glycoproteins 359 – enzymatic glycoprotein synthesis 385 – generation O-glycosidic bond 359 glycosylated cyclic arginine–glycine–aspartate (RGD) derivatives 375 glycosylation 359 – using Diels–Alder chemistry 370 – via disulfide formation 367 gonadotropin-releasing hormone agonists and antagonists 251–253 – cetrorelix 253 – degarelix 253 – gonadorelin 251, 252 j523 j Index 524 – lupron(leuprolide) 252 G-proteins 463 Grignard reagents 309 Grob fragmentation 32 guanidino group of Arg, protection of 43 – Arg precursors 45 – Arg protections (selected examples) 46 – nitration 44, 45 – protection through protonation 43 h hemolytic index (HI) 502, 503 hetero-bifunctional linkers 371 hetero Diels–Alder reaction 156 hexyl-insulin monoconjugate (HIM2) 283 high-performance liquid chromatography (HPLC) 64, 85, 110, 314, 330, 331, 333 high-throughput synthesis, of peptides 396 see also parallel peptide synthesis – directed sorting 400–402 – parallel peptide synthesis 396–400 – synthesis of peptide arrays 402–405 – – Fodo’s technology 402, 403 – – MAS technology instrument 403 – – synthesizers 405 – – technological developments 404 histo-aspartyl protease (HAP) 222 HIV GP 120 V3 domain N-glycopeptide, chemoenzymatic synthesis 352 HIV-1 protease 216 – inhibitors 133, 139 – – design and structure 217 – – potent peptidomimetic inhibitors 114 – – synthesis of 114 – prodrugs of inhibitors 219 HIV reverse transcriptase 459 homophenylalanine 202 homoserine 108 Hoveyda–Grubbs catalyst 379, 380, 382 HTLV-I protease inhibitors – as anti-AIDS drugs 221 – design and structures 221 Huisgen cycloaddition – acyclic triazole peptidomimetics 113–121 – Cu-Huisgen cycloaddition reaction 103–106 – – applications of 103 – – mechanistic consideration for 103–106 – cyclic triazole peptidomimetics 109–113 – [2þ3] cycloaddition between azides and acetylenes 102, 103 – in peptidomimetic chemistry 101 – Ru-Huisgen cycloadditions, mechanistic consideration for 103–106 – thermal cycloaddition 102 – triazole-modified peptidomimetics synthesis, building blocks for 106–109 human HeLa cells 512 hydrogen bonding, schematic representation 136, 142 a-hydroxy-b-amino acids 189 – occurence of 189 – structure of 190 – – from marine organisms 190 – – naturally occurring 190 – synthesis of 191 – – 3-amino-2-hydroxydecanoic acid and its analogs 204 – – isoserine 191–193 – – isothreonine 193–196 – – norstatines 197–204 – – phenylisoserine 197 – – synthetic demands 205 p-hydroxybestatin 208 hydroxy group of Ser, Thr, protection of 54 – protectors of 54 hydroxylysine 359 N-hydroxysuccinimide (NHS) ester 370 hypothalamic neurosecretory neurons 250 i ibotenic acid (IBO) 160 icatibant (FirazyrÒ ) 255, 256 iGluR activation, mechanism 156 imidazole group of His, protection of 45–48 – His protections 48 – Na-Bom-substituted His, preparation of 47 – unprotected His – – electrophilic substitution of indole ring of 47 – – racemization of 47 imine – from chiral aldehydes 298 – E/Z isomerization 297 indole group of Trp, protection 48, 49 – side-reactions of unprotected Trp 48 a-integrin receptor 233 intestinal drug permeability mechanisms 279 N-iodoacetyl glycosylamines 384 isocyanates 363 isocyanato peptides, synthesis of isoserine 191 isothreonine 193–196 k kanamycin 207 keyhole limpet hemocyanin (KLH) 381 Index Kinugasa reaction 314, 315 – catalysts for 315 – with Cu (II) catalyst 316 Kochetkov anomeric amination 348 Kochetkov method 343 Koenigs–Knorr reaction 364 l b-lactamase 459 b-lactams, asymmetric synthesis – arenechromium imines 302 – by azaferrocene catalyst 314 – bis-aldimines 308 – N-bis(trimethylsilyl)methyl imines 306 – N-Boc-a-aminoimines 300 – catalysts influence on stereoselectivity 309–317 – – b–lactams 106 with proton sponge 312 – – Kinugasa reaction with Cu (II) catalyst 316 – – tandem nucleophile/Lewis acid-promoted synthesis 312–314 – – trans-b-lactams 113, catalytic asymmetric synthesis of 314–316 – with chiral catalysts 312 – chiral imines 302 – chiral substituents influence on stereoselectivity 298 – double asymmetric cycloinduction 308, 309 – Evans-Sjögren ketenes 309 – imine 301, 303, 304 – – component, asymmetric induction 298–305 – – geometry influence on stereoselectivity 294, 295 – – isomerization influence, nucleophilic attack onto ketene stereoselectivity 296, 297 – ketene 301, 303, 304 – – component, asymmetric induction 305–308 – Lewis acid/nucleophile synthesis 313 – order of addition influence of reactants 297, 298 – solvent polarity influence on stereoselectivity 296 – symmetrical/unsymmetrical ketimines 307 – unsubstituted imines 307 – via Staudinger reaction (see Staudinger reaction) Lansbury method, for glycopeptides 342 b-letosulfide 201 leucine aminopeptidase 208 ligand-binding domain (LBD) 155 lipid dendrimer 508, 510 lysine side-chains modifications 368–370 m macrocyclic human renin inhibitors 215 macrocyclic peptidomimetics 133–135 macro-lactonization strategy 113 magnetic resonance imaging (MRI) 505, 506, 513 matrix-assisted laser desorption ionization (MALDI)-MS 413 membrane-bound glycoprotein mucin (MUC1) 325 4-mercaptophenylacetic acid 378 O-mesitylenesulfonylhydroxylamine (MSH) 368 metalloaminopeptidases (MAPs) 208 metallopeptidases 208 metalloproteases 465 methanethiosulfonate (MTS) 367 p-methoxy benzyl (PMB) 346 4-methoxyphenacyloxycarboxyl (Phenoc) 57 N-methyl-a-amino acids (NMAs) 7, 22 4-methylbenzhydrylamine (MBHA) resin 110 p-methylbestatin 208 methyl (S)-Boc-d-azido-norvalinate synthesis 109 N-methyl-D-aspartic acid (NMDA) receptors 151 methyl esters 35, 36 – group, structure–activity relationship 185 N-methylmorpholine (NMM) 31, 203, 233, 363 4-methylpiperidine 399 methylsulfenyl triflate (MeSOTf) 326 7-methyl-,5,7-triaza-bicyclo[4.4.0]dec-5-ene (MTBD) 34 Michael acceptor 368 Michael addition–cyclization process 304, 305 Michaelis–Menten kinetics 504 microsclerodermin A 190 Mitsunobu reaction 108 monocyclization 110 mucin-type glycopeptides synthesis – glycopeptide vaccines synthesis 325–331 – – MUC1–OVA glycopeptide vaccines 330 – – reagents and conditions 326–329 – P-selectin glycoprotein ligand-1 synthesis, glycopeptide recognition domain 331–339 – – PSGL-1 glycopeptides 337–339 – – reagents and conditions 334, 335 j525 j Index 526 – – sialyl-T antigen–BSA conjugate 332, 333 – – T antigen–BSA conjugate 332, 333 – structure 322, 323 – tumor-associated glycopeptides 325–331 – – reagents and conditions 326–329 mucosal cell permeability 278 MUC1–OVA glycopeptide vaccines, synthesis 330 multicomponent reactions (MCRs) multidrug-resistant (MDR) gram-negative pathogens 266 multiple antigenic peptides (MAPs) synthesis 497–500 – designs 500 – initial efforts on 502 – ligating unprotected peptides, chemoselective methods for 499 – schematic diagram for 498 multivalency effect, thermodynamic model 499 p-nitrophenyl anthranilate (PNPA) 371 nonsymmetric dendrimers 507 nuclear magnetic resonance (NMR) spectroscopy 116, 120, 133 n p Na-Dts-protected amino acids Na-Dts protection, thiolytic cleavage of Na,Na–bis-protected amino acids 32 Na-Nps-protected amino acids 13 Na-Phth-amino acids Na–protected peptide acid Na–protecting groups 32 – in synthesis of NMAs 33, 34 Na protection see a-amino protection Na-sub-amino acids 12 native chemical ligation (NCL) 343 Na-Trt-protected amino acids 12 natural peptides, degradation 248 natural proteins 473 Na-urethane protections, interconversion of 31 neoglycopeptide 360, 361 – application, as synthetic vaccines 380–384 – C-glycosides 365 – C¼N linkage 365, 366 – N-glycosides 362–364 – O-glycosides 364 – S-glycosides 361, 362 – via CuAAC 373–376 neoglycoproteins 361 – CuAAC and 376–378 nesiritide (NatrecorÒ ) 249 neurotensin – structure 270 – tetra-branched forms 269 p-nitrobestatin 208 o OctreoscanÔ 262, 263 octreotide 260, 261 Ojima–Holton b-lactam coupling method 197 oligopeptides 1, – as antibacterial agents 205 – binds toavb3 integrins 506 – formation, during introduction of Naurethane protections 30 – reaction mechanism for formation of 30 – transporter (PEPT1) 281 one-pot Na protection 33 oxazolidinone 34 oxytocin 249, 250 ozonolysis 364 paclitaxel – analogs, clinical trials 231 – and derivatives 228 – – DAB 228 – – docetaxel 228 – plasmin-sensitive prodrug 233 – prodrugs in advanced, clinical trials 232 – structure of 228 – synthesis – – of IDN 5109 and SB-T-1214 229 – – of isotaxel and release mechanism of paclitaxel 231 – – of 3’-N-acyl-paclitaxel analogs 230 – – and release mechanism of paclitaxel plasmin-sensitive prodrug 233 – – route for paclitaxel analogs 229, 231 parallel peptide synthesis 396 – diketopiperazine linker release 398 – Frank’s synthesis on paper circles 396 – Geysen’s pin synthesis 397 – – use of lanterns 397 – Houghten’s technique of tea-bag synthesis 397 – new instruments 398–400 – – centrifugal DNA and peptide synthesizer 399 – – TetrasÔ 398 – peptide cleavage from solid support 397, 398 parathyroid hormone 256, 257 Index peptide dendrimers see also amino acid-based dendrimers – applications – – as antimicrobial agents 502–504 – – as DNA/RNA delivery vectors 507–512 – – initial efforts on MAPs 502 – – ion sensors and MRi contrast agents 505–507 – – as protein/enzyme mimics 504, 505 – catalysis of ester hydrolysis 504 – synthesis 491–502 – – of cyclic peptide dendrimers 500 – – glutamic/aspartic acid, proline, and arginine dendrimers 494–497 – – grafted on PAMAM 500–502 – – MAPs synthesis 497–500 – – polylysine dendrimers synthesis 493 peptide drugs – antimicrobial peptides 263–267 – – Daptomycin 266 – – Gramicidin S 267 – – Polymyxin 265, 266 – availablity in market 249–258 – – antihyperglycemics 254, 255 – – blood coagulation inhibitors 251 – – calcitonin 256 – – cyclosporine 257 – – desmopressin 251 – – fuzeon 257, 258 – – gonadotropin-releasing hormone agonists and antagonists 251–253 – – icatibant 255, 256 – – natriuretic peptide (Nesiritide) 249 – – oxytocin 249, 250 – – parathyroid hormone 256, 257 – – sermorelin 256 – – vasopressin 250 – intestinal absorption, fundamental considerations 277–279 – oncology, approved peptides in 258–263 – – actinomycin D 259, 260 – – bortezomib 259 – – narimastat 260 – – OctreoscanÔ 262, 263 – – octreotide 260, 261 – – vapreotide 261, 262 – oral bioavailability 277 – – formulation technologies 284–287 – – improvement strategies 280–287 – – limiting barriers 279–280 – perspectives 267–270 – – branched peptides as antimicrobials 270 – – branched peptides as tumor-targeting agents 268–270 peptide libraries – future of 421 – omission libraries 408 – orthogonal libraries 408, 409 – peptide mixtures, synthesis of 406–409 – positional scanning libraries 406 – solution-based screening, of OBOC libraries 418–421 – synthesis of peptides, on mixture of particles 409–416 – – automated bead picking system 414 – – bead sorting instrument for OBOC 413 – – determination of structure of peptide on 416–418 – – hit isolation through magnetic bead sorting 412 – – one-bead–one-compound (OBOC) technology 409, 410, 415 – – one-bead–two-compounds assay 411 – – synthesis of hexapeptide library 416 – – validation 413 – synthetic protocols 421 – – dual-layer beads, preparation of 425, 426 – – library of libraries, preparation of 426 – – OBOC libraries for testing in solution, preparation of 426–431 – – pin synthesis 421, 422 – – split-and-mix synthesis of OBOC noncleavable libraries 424, 425 – – SPOT synthesis 422 – – synthesis in tea-bags 422, 423 – – synthesis on cotton 423, 424 peptides 1, 11, 20, 29, 35, 38 – antimicrobial 263, 264, 270, 502, 503 – biostability of 249 – cationic 265, 270 – combinatorial 458, 459, 461, 465 – containing difficult sequences as useful tool for 220 – crude 423 – dendrimeric 502 – as drugs 249 – library (see peptide libraries) – natural 248 – oligo-branched 268 – synthesis using cystine as self-protected Cys 51–53 – tetra-branched neurotensin 270 – therapeutic 264 – Z group-protected 82 peptidomimetic drugs j527 j Index 528 – intestinal absorption, fundamental considerations 277–279 – oral bioavailability 277 – – limiting barriers 279, 280 Perlman’s catalyst 306 Peyer’s patches 286 phage vectors 452 – combinatorial peptide libraries, generation of 455–458 – – Kunkel mutagenesis approach 457 – – modified protocol 456, 457 – M13 bacteriophage 452, 453 – phage-displayed combinatorial peptide libraries – – advantages 452 – – alanine scanning for 460 – – disadvantages 452 – – identifying peptide ligands – – binding to cell surfaces 463, 464 – – to surfaces of inert materials 465 – – mapping protease specificity 464, 465 – – mapping protein–protein interactions 461–463 – – phage ELISA 461 – – screening, for peptide ligands to target proteins 458–460 – phage-display particles, types of 453 – – type or displaying, combinatorial peptides 453, 454 phebestin 210, 211 phenolic group of Tyr, protection 54 – protectors of 55 phenylisoserine 197 phenylnorstatine 197 phenylthiosulfonate (PTS) 367 phosphoadenosyl phosphosulfate (PAPS) 336 photocleavable carboxy protectors 57 photocleavable protections 57 – advantages of 57 phthaloylating reagents plasmepsin II inhibitors 222–224 Plasmodium falciparum 222 poly(amido amine) (PAMAM) dendrimers 491, 500, 501 – synthesis 501 polylysine dendrimers synthesis 493 Polymyxins 265, 266 polypeptides – linear 513 – Na-deprotection 14 polypropylene imine (PPI) 491 post-translational modifications probestin 211 prodrug approach, for oral bioavailability of peptide-based drugs 280, 281 prostate-specific antigen 465 protease inhibitors 285 protease–ligand complexes 132 proteases 462, 464 protection reactions 2, 59 – general procedure, for preparation of 59 – – amino acid benzyl ester p-toluenesulfonate salts 70, 71 – – amino acid ethyl esters 69, 70 – – amino acid methyl ester hydrochloride salts 68, 69 – – amino acids using pentafluorophenyl carbonate 80, 81 – – tert-butyl esters of Na-unprotected amino acids 71–80 – – Na-Aloc-amino acids 65 – – Na-Boc-amino acids 65–67 – – Na-Bpoc-amino acids 67, 68 – – Na-Bsmoc-amino acids 64, 65 – – Na-Fmoc-amino acids 62–64 – – Na-Ns-amino acids 60 – – Na-Nsc-amino acids 64 – – Na–phthaloyl amino acids using N(ethoxycarbonyl)phthalimide 59 – – Na–Trt-amino acids 59, 60 – – Na-Z-amino acids 61 – – Tfa-Arg-OH 59 protectors – of hydroxy group of Ser/Thr 54 – of phenolic function of Tyr 55 protein design methods 475, 476 – computational design 476, 477 – – computational enzyme design 477, 478 – – results of computational design experiments 478–480 – – b-barrel 478, 479 – – b-sheets 478, 479 – – TIM-barrel 478, 479 – – top7 479 – directed evolution methods 480 – – expression systems and assays 481, 482 – – randomization strategies 480, 481 protein design, protocol for 484–486 – RosettaDesign 485, 486 – RosettaHoles method 486 protein interfaces, design of 482–484 proteinogenic amino acid protein–protein interactions 461, 463 protein side-chain modifications 366 – modifications of – – cysteine side-chains 366–368 Index – – fluorescent anthranilamide-linked glycoconjugate 371 – – hetero-bifunctional linkers 371 – – lysine side-chains 368–370 protein structure databases 474 P-selectin glycoprotein ligand-1 (PSGL-1) 331 – chemoenzymatic synthesis 338, 339 – synthesis 337 Pseudomonas aeruginosa 503 pyridinum chlorochromate (PCC) 201 q (S)-quisqualic acid (QUIS) 160 Quisqualis indica 160 r racemization 6, – and b-elimination in S-protected Cys residues 53 – of Na-acyl-a-amino acid derivatives recombinant DNA technology 248 reductive amination 364 regioselectively addressable functionalized templates (RAFTs) 365 renin–angiotensin system (RAS) 212 restriction process 153 retro-synthetic analysis 155 ribosomes 1, 205 RNase C enzyme 345 RNase C glycoprotein – synthesis 344, 345 – – fragments 344 – – through NCL 345 RNase fragment 344 rotating-frame Overhauser spectroscopy (ROESY) 137 ruthenium-catalyzed Huisgen cycloaddition 103 – mechanistic consideration for 103–106 – Ru-catalysts, synthesis of 105 s Schlerochiton ilicifolius 153 scytonemin A 190, 191 secondary amide bond self-assembling backbone modified peptidomimetics 112 serine 108, 321, 326, 340, 359, 381, 407, 421 serine proteases 465 sermorelin 256 severe combined immunodeficiency (SCID) 186 sialic acid 321 sialyl-T antigen–BSA conjugate synthesis 332, 333 side-chain protection – o-amido group of Asn and Gln 49, 50 – o-amino group of diamino acids 41–44 – guanidino group of Arg 43 – – Arg precursors 45 – – nitration 44, 45 – – protection through protonation 43 – imidazole group of His 45–48 – indole group of Trp 48, 49 – b-thiol group of Cys 50, 51 silyl ester protection 41 solid-phase chemistry 395 solid-phase peptide synthesis (SPPS) 4, 360, 395 solid-phase synthesis 104, 116 split-and-mix combinatorial peptide dendrimer library 505 S-protected cys derivatives, common side-reactions with 51 – o-carboxy group of Asp and Glu 55 – – aspartimide formation 55–57 – b-elimination 51 – hydroxy group of Ser, Thr, and phenolic group of Tyr 54 – – protectors of the hydroxy group of Ser/Thr 54 – – protectors of the phenolic function of Tyr 55 – oxidation 51 – racemization 51 – synthesis of peptides using cystine as self-protected Cys 51–53 – thioether group of Met 53, 54 standard Kaiser test 122 Staudinger reaction 293, 294 see also b-lactams, asymmetric synthesis – asymmetric induction – – from imine component 298–305 – – from ketene component 305–308 – chiral catalysts for 311 – diastereoisomeric excess 296 – double asymmetric cycloinduction 308, 309 – influence of – – catalysts on stereoselectivity 309–312 – – chiral substituents on 298 – – geometry of imine on stereoselectivity in 294, 295 – – isomerization of imine 296, 297 – – polarity of solvent on 296 j529 j Index 530 – mechanism 294, 311 – reduction approach 122 – stereochemistry of 295 b-strand mimetics – acyclic compounds 135, 136 – aliphatic and aromatic carbocycles 136, 137 – ligands containing – – one/multiple rings with one heteroatom 138, 139 – – one ring with one heteroatom 137, 138 – – one ring with two heteroatoms 139 – – one ring with two/three heteroatoms 140 – – two rings with one heteroatom 140, 141 – – two rings with two/three heteroatoms 141, 142 – macrocyclic peptidomimetics 133–135 – recent advances in 129 – b–sheets 130 – b–strands 129 – – composed of Ala residues 130 – strand/sheet/turn/helix recognition, differences in 130, 131 – towards b-strand mimetics 131–133 Streptomyces olivoreticuli 207 structure–activity studies 162–168, 178 – case studies – – AMPA analogs 162, 163 – – 4-substituted Glu analogs 163–168 – – binding affinities of 4-alkylGlu analogs at native iGluRs and 165–167 – – DPAG, selective inhibitor of the EAAT2 subtype 168 substituted benzyl esters 38 sulfosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfoSMCC) 370 synthesized peptides, sequences and structures 509 synthetic glycopeptides 324 synthetic peptides t tachykinin NK1 receptor antagonists 185 target protein 247 L-tartaric acid 204 Taxus baccata 228 T cells 383 temporary a acarboxy protection 39, 41 tetrahydrofuran (THF) 104, 343 tetra-n-butylammonium fluoride (TBAF) 333 tetrathiomolybdate salt 32 tetravalent RAFT glycoclusters 366 thermal Huisgen cycloaddition 102 thioether group of Met, protection 53 – through oxidation 53 N-thioformyl glycosides 363 thioibotenic acid (TIBO) – chemical structures of 161 – design and synthesis 161, 162 b-thiol protections of Cys 52 threonine 359 – mutant dendrimer 505 tilidine synthesis 184 tissue-type plasminogen activator 465 transesterification 200 triazoles 101 – 1H-triazole-CH NMR resonances 121 – linked AFGP analogs 376 – modified peptidomimetics synthesis, building blocks for 106–109 – as peptide bond isosteres 102 – peptidomimetic, synthesis 117 – 1,4-triazoles – – b-turn-induced 115 – – use of 111 – trimer, solution-phase synthesis 116 – uses of 116 triethylamine (TEA) 9, 191, 421 trifluoroacetic acid (TFA) 5, 157, 215, 326, 419, 493 trifluoroacetic anhydride (TFAA) 5, 7, 59 tris-[(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) 104 tris(2-carboxyethyl)phosphine (TCEP) 344, 345, 350, 378 trypsin variants 465 tumor-targeting agents 258 tumor-targeting drugs 268 tyrosine 331, 336, 359, 421 u ubenimex 205, 209 ubiquitin 484 unprotected amino acids urea-linked glycosides 363 urethanes – bond formation 15–17 – cleavage 17–19 – – by b-elimination 19 – derived from primary alcohols 15 – – allyloxycarbonyl (Aloc) group 25 – – benzyloxycarbonyl (Cbz or Z) group 15–19 – – cleaved by b-elimination 19–24 – – cleaved via Michael-type addition 24 – derived from, secondary alcohols 25 Index – derived from, tertiary alcohols 25 – – Boc analogs 28, 29 – – tert-butoxycarbonyl (Boc) group 25, 26 – – deprotection 27 – – lewis acids 28 – – organosilanes 28 – – oxidizing agent 28 – – preparation 26, 27 – – protic acids 27 – – removal of Boc groups 28 – modes of fission 15 – protected NCAs 31 – protectors – – formation of dipeptide impurities during 29, 30 – – nitrogen of a-amino acid N-carboxy anhydrides (NCAs), protection of 31 – – urethanes via transprotection, introduction of 30, 31 – structure 15 US Food and Drug Administration (FDA) 253, 256, 260, 264, 266 v vapreotide 261 vascular endothelial growth factor receptor (VEGFR1) 110 – potential VEGFR1 antagonists, synthesis of 111 vasopressin 250 Veber–Hirschmann cyclic hexapeptide cyclo (-PFwKTF-) 283 w Wang resin 329 Weinreb amide derivatives 108 (S)-willardiine (WILLA) 160 Willebrand factor 251 x X-ray crystallography 177, 461 X-ray crystal structure analysis 101 – of peptidomimetics 115 z zwitterionic intermediate 295 j531 [...]... large number of analogs Consequently, the major proportion of the Amino < /b> Acids, < /b> Peptides < /b> and < /b> Proteins < /b> in < /b> Organic < /b> Chemistry < /b> Vol .4 < /b> – Protection < /b> Reactions, < /b> Medicinal < /b> Chemistry, /b> Combinatorial < /b> Synthesis < /b> Edited by Andrew < /b> B Hughes Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32103-2 j 1 Protection < /b> Reactions 2 demand for peptides < /b> is still met by chemical synthesis < /b> Chemical synthesis.< /b> .. Brisbane, Queensland 40< /b> 72 Australia Chiara Falciani University of Siena Department of Biotechnology Laboratory of Molecular Biotechnology Via Fiorentina 1 53100 Siena Italy Amino < /b> Acids, < /b> Peptides < /b> and < /b> Proteins < /b> in < /b> Organic < /b> Chemistry < /b> Vol .4 < /b> – Protection < /b> Reactions, < /b> Medicinal < /b> Chemistry, /b> Combinatorial < /b> Synthesis < /b> Edited by Andrew < /b> B Hughes Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim ISBN: 978-3-527-32103-2... Synthetic Protocols 42< /b> 1 Pin Synthesis < /b> 42< /b> 1 SPOT Synthesis < /b> 42< /b> 2 Synthesis < /b> in < /b> Tea-Bags 42< /b> 2 Synthesis < /b> on Cotton 42< /b> 3 Modification of the Cotton Carrier 42< /b> 3 Split -and-< /b> Mix Synthesis < /b> of OBOC Noncleavable Libraries 42< /b> 4 Preparation of Dual-Layer Beads 42< /b> 5 Preparation of Library of Libraries 42< /b> 6 Preparation of OBOC Libraries for Testing in < /b> Solution 42< /b> 6 Synthesis < /b> of Multicleavable Linker 42< /b> 6 Synthesis < /b> of the Library... Acid and < /b> its Analogs 2 04 < /b> Synthetic Demands 205 Antibacterial Agents 205 Inhibitors of Aminopeptidases 207 Aspartyl Proteases Inhibitors 211 Renin Inhibitors 212 HIV-1 Protease Inhibitors 216 HTLV-I Inhibitors 220 Plasmepsin II Inhibitors 222 BACE-1 Inhibitors 2 24 < /b> Paclitaxel and < /b> its Derivatives 228 References 2 34 < /b> Peptide Drugs 247< /b> Chiara Falciani, Alessandro Pini, and < /b> Luisa Bracci Lights and < /b> Shades... + CH2 O 1 R O R = Bzl HX acidolysis H O R O N R H N R1 H R= Bzl or tert-butyl H OH CH2 R1 NH2 + CO2 R O H R = Bzl N R1 H R= tert-butyl SN1 2 X SN SN1 H X + RNH-COOH X + RNH-COOH CH2 + RNH-COOH X H H X RNH3 + CO2 RNH3 + CO2 X RNH3 + CO2 type B H R1 base H N O O base R1 R -H H N O R H R1 + NH2-R O Figure 1.20 Reaction conditions for cleavage of urethane protections Type A: benzyl and < /b> tert-butyl urethanes... coupling step to obtain a free amino < /b> group for subsequent acylation and,< /b> hence, this protection < /b> is temporary The carboxy and < /b> side-chain protections are generally retained until the entire sequence 1.1 General Considerations route 1 R2 R1 amino < /b> protection < /b> COOH H 2N j3 R1 H2 N X PgHN COOH PgHN R1 carboxy activation amino < /b> acid B route 2 R 2 H2 N carboxy group protection < /b> COOH H2 N H N PgHN coupling O amino.< /b> .. the adjacent groups or, if it does, it should be in < /b> predictable ways R NH2 R: 4 < /b> Lys H N 3 NH2 H2 N H N HN His OH O NH2 N NH Arg H COOH OH OH S COOH SH n=1,2 n=1,2 Trp n = 1: Asn n = 2: Gln Ser Thr Tyr Figure 1.2 Side-chain functional groups of amino < /b> acids that entail protection < /b> Cys Met n = 1: Asp n = 2: Glu j 1 Protection < /b> Reactions 4 < /b> In < /b> this chapter, various a -amino,< /b> carboxy, and < /b> side-chain protecting... Figure 1.7 Phthaloylating reagents 3-chloro-3-(dimethoxyphosphoryl)isobenzofuran-1( 3H) -one 15 [10] N-Phthaloylation by these reagents has almost completely replaced the original and < /b> harsh route of fusing amino < /b> acids with phthalic anhydride, which invariably caused racemization An improvement in < /b> the method was achieved by using solvents such as benzene, dioxane, and < /b> so on, but could not overcome the racemization... removed by treatment with dilute AcOH or 0 .4 < /b> M HCl in < /b> THF or 0.1 M R HCl H2 N COOMe a) Sub-Cl,TEA CH2Cl2 rt b) 2M NaOH MeOH reflux Figure 1.15 Preparation of Na-Sub -amino < /b> acids R N H COOH 32 1.2 a -Amino < /b> Protection < /b> (Na Protection)< /b> R O N H CO -2HBr O H 2O N Br 33 R R 2Br2 CO O Br O Br + H2 N Br Figure 1.16 Cleavage of the Na-Dim group by bromination TosOH in < /b> THF [ 34]< /b> The Na-vinyl derivatives are not prone to... Evolution Methods 48< /b> 0 Randomization Strategies 48< /b> 0 Expression Systems and < /b> Assays 48< /b> 1 Design of Protein Interfaces 48< /b> 2 Protocol for Protein Design 48< /b> 4 Conclusions 48< /b> 6 References 48< /b> 7 47< /b> 8 Amino < /b> Acid-Based Dendrimers 49< /b> 1 Zhengshuang Shi, Chunhui Zhou, Zhigang Liu, Filbert Totsingan, and < /b> Neville R Kallenbach Introduction 49< /b> 1 Peptide Dendrimer Synthesis:< /b> Divergent and < /b> Convergent Approaches 49< /b> 1 Synthesis < /b> of the First