Amino Acids, Peptides and Proteins in Organic Chemistry -  - ebook

Amino Acids, Peptides and Proteins in Organic Chemistry ebook

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This is the fourth of five books in the Amino Acids, Peptides and Proteins in Organic Synthesis series. Closing a gap in the literature, this is the only series to cover this important topic in organic and biochemistry. Drawing upon the combined expertise of the international "who's who" in amino acid research, these volumes represent a real benchmark for amino acid chemistry, providing a comprehensive discussion of the occurrence, uses and applications of amino acids and, by extension, their polymeric forms, peptides and proteins. The practical value of each volume is heightened by the inclusion of experimental procedures. The fourth volume in this five-volume series is structured in three main sections. The first section is about protection reactions and amino acid-based peptidomimetics. The second, and most extensive, part is devoted to the medicinal chemistry of amino acids. It includes, among others, the chemistry of alpha- and beta amino acids, peptide drugs, and advances in N- and O-glycopeptide synthesis. The final part deals with amino acids in combinatorial synthesis. Methods, such as phage display, library peptide synthesis, and computational design are described.

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Contents

Cover

Further Reading

Title Page

Copyright

List of Contributors

Chapter 1: Protection Reactions

1.1 General Considerations

1.2 α-Amino Protection (Nα Protection)

1.3 Carboxy Protection

1.4 Side-Chain Protection

1.5 Photocleavable Protections

1.6 Conclusions

1.7 Experimental Procedures

Acknowledgments

References

Part One: Amino Acid-Based Peptidomimetics

Chapter 2: Huisgen Cycloaddition in Peptidomimetic Chemistry

2.1 Introduction

2.2 Huisgen [2 + 3] Cycloaddition Between Azides and Acetylenes

2.3 Mechanistic Consideration for the Cu-Huisgen and Ru-Huisgen Cycloadditions

2.4 Building Blocks for the Synthesis of Triazole-Modified Peptidomimetics

2.5 Cyclic Triazole Peptidomimetics

2.6 Acyclic Triazole Peptidomimetics

2.7 Useful Experimental Procedures

References

Chapter 3: Recent Advances in b-Strand Mimetics

3.1 Introduction

3.2 Macrocyclic Peptidomimetics

3.3 Acyclic Compounds

3.4 Aliphatic and Aromatic Carbocycles

3.5 Ligands Containing One Ring with One Heteroatom (N)

3.6 Ligands Containing One or Multiple Rings with One Heteroatom (O, S)

3.7 Ligands Containing One Ring with Two Heteroatoms (N,N)

3.8 Ligands Containing One Ring with Two Heteroatoms (N,S) or Three Heteroatoms (N,N,S or N,N,N)

3.9 Ligands Containing Two Rings with One Heteroatom (N or O)

3.10 Ligands Containing Two Rings with Two or Three Heteroatoms (N,N or N,S or N,N,N)

3.11 Conclusions

References

Part Two: Medicinal Chemistry of Amino Acids

Chapter 4: Medicinal Chemistry of α-Amino Acids

4.1 Introduction

4.2 Glutamic Acid

4.3 Conformational Restriction

4.4 Bioisosterism

4.5 Structure–Activity Studies

4.6 Conclusions

References

Chapter 5: Medicinal Chemistry of Alicyclic β-Amino Acids

5.1 Introduction

5.2 Five-Membered Alicyclic β-Amino Acids

5.3 Six-Membered Alicyclic β-Amino Acids

References

Chapter 6: Medicinal Chemistry of α-Hydroxy-β-Amino Acids

6.1 Introduction

6.2 α-Hydroxy-β-Amino Acids

6.3 Antibacterial Agents

6.4 Inhibitors of Aminopeptidases

6.5 Aspartyl Proteases Inhibitors

6.6 Paclitaxel and its Derivatives

References

Chapter 7: Peptide Drugs

7.1 Lights and Shades of Peptide and Protein Drugs

7.2 Peptide Drugs Available on the Market

7.3 Approved Peptides in Oncology

7.4 Antimicrobial peptides

7.5 Perspectives

References

Chapter 8: Oral Bioavailability of Peptide and Peptidomimetic Drugs

8.1 Introduction

8.2 Fundamental Considerations of Intestinal Absorption

8.3 Barriers Limiting Oral Peptide/Peptidomimetic Drug Bioavailability

8.4 Strategies to Improve Oral Bioavailability of Peptide-Based Drugs

8.5 Conclusions

References

Chapter 9: Asymmetric Synthesis of β-Lactams via the Staudinger Reaction

9.1 Introduction

9.2 Staudinger Reaction

9.3 Influence of the Geometry of the Imine on Stereoselectivity in the Reaction

9.4 Influence of the Polarity of the Solvent on Stereoselectivity of the Reaction

9.5 Influence of the Isomerization of the Imine Prior to its Nucleophilic Attack onto the Ketene Stereoselectivity in the Reaction

9.6 Influence of the Order of Addition of the Reactants to the Reaction

9.7 Influence of Chiral Substituents on the Stereoselectivity of the Reaction

9.8 Asymmetric Induction from the Imine Component

9.9 Asymmetric Induction from the Ketene Component

9.10 Double Asymmetric Cycloinduction

9.11 Influence of Catalysts on the Stereoselectivity of the Reaction

9.12 Conclusions

References

Chapter 10: Advances in N- and O-Glycopeptide Synthesis – A Tool to Study Glycosylation and Develop New Therapeutics

10.1 Introduction

10.2 Synthesis of O-Glycopeptides

10.3 Synthesis of N-Glycopeptides

References

Chapter 11: Recent Developments in Neoglycopeptide Synthesis

11.1 Introduction

11.2 Neoglycoside and Neoglycopeptide Synthesis

11.3 Protein Side-Chain Modifications

11.4 Cu(I)-Catalyzed Azide–Alkyne “Click” Cycloaddition

11.5 Cross-Metathesis

11.6 Application of Neoglycopeptides as Synthetic Vaccines

11.7 Enzymatic, Molecular, and Cell Biological Techniques

References

Part Three: Amino Acids in Combinatorial Synthesis

Chapter 12: Combinatorial/Library Peptide Synthesis

12.1 Introduction

12.2 High-Throughput Synthesis of Peptides

12.3 Synthesis of Peptide Arrays

12.4 Peptide Libraries

12.5 Future of Peptide Libraries

12.6 Synthetic Protocols

References

Chapter 13: Phage-Displayed Combinatorial Peptides

13.1 Introduction

13.2 Conclusions

References

Chapter 14: Designing New Proteins

14.1 Introduction

14.2 Protein Design Methods

14.3 Protocol for Protein Design

14.4 Conclusions

References

Chapter 15: Amino Acid-Based Dendrimers

15.1 Introduction

15.2 Peptide Dendrimer Synthesis: Divergent and Convergent Approaches

15.3 Applications of Peptide Dendrimers

15.4 Conclusions

References

Index

Further Reading

Pignataro, B. (ed.)

Ideas in Chemistry and Molecular Sciences

Advances in Synthetic Chemistry

2010

ISBN: 978-3-527-32539-9

Theophil Eicher, Siegfried Hauptmann and Andreas Speicher

The Chemistry of Heterocycles

Structure, Reactions, Synthesis, and Applications

2011

ISBN: 978-3-527-32868-0 (Hardcover)

ISBN: 978-3-527-32747-8 (Softcover)

Royer, J. (ed.)

Asymmetric Synthesis of Nitrogen Heterocycles

2009

ISBN: 978-3-527-32036-3

Reek, J. N. H., Otto, S.

Dynamic Combinatorial Chemistry

2010

ISBN: 978-3-527-32122-3

Rutjes, F., Fokin, V. V. (eds.)

Click Chemistry

in Chemistry, Biology and Macromolecular Science

2011

ISBN: 978-3-527-32085-1

Drauz, K., Gröger, H., May, O. (eds.)

Enzyme Catalysis in Organic Synthesis

Third, completely revised and enlarged edition

3 Volumes

2011

ISBN: 978-3-527-32547-4

Fessner, W.-D., Anthonsen, T.

Modern Biocatalysis

Stereoselective and Environmentally Friendly Reactions

2009

ISBN: 978-3-527-32071-4

Lutz, S., Bornscheuer, U. T. (eds.)

Protein Engineering Handbook

2 Volume Set

2009

ISBN: 978-3-527-31850-6

Sewald, N., Jakubke, H.-D.

Peptides: Chemistry and Biology

2009

ISBN: 978-3-527-31867-4

Jakubke, H.-D., Sewald, N.

Peptides from A to Z

A Concise Encyclopedia

2008

ISBN: 978-3-527-31722-6

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)

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 do 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.

ISBN: 978-3-527-32103-2

List of Contributors

Andrew David Abell

University of Adelaide

School of Chemistry and Physics

North Terrace

Adelaide, South Australia 5005

Australia

Gordon L. Amidon

University of Michigan

College of Pharmacy

Department of Pharmaceutical Sciences

428 Church Street

Ann Arbor, MI 48109

USA

Luisa Bracci

University of Siena

Department of Biotechnology

Laboratory of Molecular Biotechnology

Via Fiorentina 1

53100 Siena

Italy

Margaret A. Brimble

University of Auckland

Department of Chemistry

23 Symonds Street

1043 Auckland

New Zealand

Lennart Bunch

University of Copenhagen

Faculty of Pharmaceutical Sciences

Department of Medicinal Chemistry

Universitetsparken 2

2100 Copenhagen

Denmark

Arik Dahan

Ben-Gurion University of the Negev

School of Pharmacy

Faculty of Health Sciences

Department of Clinical Pharmacology

Beer-Sheva 84105

Israel

David P. Fairlie

University of Queensland

Institute for Molecular Bioscience

Division of Chemistry and Structural

Biology

306 Carmody Rd

Brisbane, Queensland 4072

Australia

Chiara Falciani

University of Siena

Department of Biotechnology

Laboratory of Molecular Biotechnology

Via Fiorentina 1

53100 Siena

Italy

Nils Griebenow

Bayer Schering Pharma

Medicinal Chemistry

Aprather Weg 18a

42096 Wuppertal

Germany

Renhua Huang

University of Illinois at Chicago

Department of Biological Sciences

845 W. Taylor Street

Chicago, IL 60607-7060

USA

Neville R. Kallenbach

New York University

Department of Chemistry

100 Washington Square East

New York, NY 10003-5180

USA

Brian K. Kay

University of Illinois at Chicago

Department of Biological Sciences

845 W. Taylor Street

Chicago, IL 60607-7060

USA

Yoshiaki Kiso

Kyoto Pharmaceutical University

Center for Frontier Research in

Medicinal Science

Department of Medicinal Chemistry

21st Century COE Program

Yamashina-ku

607-8412 Kyoto

Japan

Malgorzata Kokoszka

University of Illinois at Chicago

Department of Biological Sciences

845 W. Taylor Street

Chicago, IL 60607-7060

USA

Monika I. Konaklieva

American University

Department of Chemistry

4400 Massachusetts Avenue, NW

Washington, DC 20016

USA

Povl Krogsgaard-Larsen

University of Copenhagen

Faculty of Pharmaceutical Sciences

Department of Medicinal Chemistry

Universitetsparken 2

2100 Copenhagen

Denmark

Horst Kunz

Johannes Gutenberg-Universität

Institut für Organische Chemie

Duesbergweg 10–14

55128 Mainz

Germany

Michal Lebl

Institute of Organic Chemistry and

Biochemistry AS CR

Department of Peptide Chemistry

Flemingovo nam 2

166 10 Praha 6

Czech Republic

Zhigang Liu

New York University

Department of Chemistry

100 Washington Square East

New York, NY 10003-5180

USA

Wendy A. Loughlin

Griffith University

Science, Engineering, Environment and

Technology Group

Nathan Campus N55 Kessels Rd

Brisbane, Queensland 4111

Australia

James T. MacDonald

Medical Research Council

National Institute for Medical Research

The Ridgeway, Mill Hill

London NW7 1AA

UK

Jonathan M. Miller

University of Michigan

College of Pharmacy

Department of Pharmaceutical Sciences

428 Church Street

Ann Arbor, MI 48109

USA

Nicole Miller

University of Auckland

Department of Chemistry

23 Symonds Street

1043 Auckland

New Zealand

Narasimhamurthy Narendra

Bangalore University

Department of Studies in Chemistry

Central College Campus

Dr. B.R. Ambedkar Veedhi

Bangalore 560001

Karnataka

India

Daniel Sejer Pedersen

University of Copenhagen

Faculty of Pharmaceutical Sciences

Department of Medicinal Chemistry

Universitetsparken 2

2100 Copenhagen

Denmark

Kritika Pershad

University of Illinois at Chicago

Department of Biological Sciences

845 W. Taylor Street

Chicago, IL 60607-7060

USA

Alessandro Pini

University of Siena

Department of Biotechnology

Laboratory of Molecular Biotechnology

Via Fiorentina 1

53100 Siena

Italy

Balbina J. Plotkin

Midwestern University

Department of Microbiology and

Immunology

555 31st Street

Downers Grove, IL 60515

USA

Michael I. Sadowski

Medical Research Council

National Institute for Medical Research

The Ridgeway, Mill Hill

London NW7 1AA

UK

Zhengshuang Shi

New York University

Department of Chemistry

100 Washington Square East

New York, NY 10003-5180

USA

Mariusz Skwarczynski

The University of Queensland

School of Chemistry and Molecular

Biosciences

St Lucia, Brisbane, Queensland 4072

Australia

Jing Sun

University of Michigan

College of Pharmacy

Department of Pharmaceutical Sciences

428 Church Street

Ann Arbor, MI 48109

USA

Vommina V. Sureshbabu

Bangalore University

Department of Studies in Chemistry

Central College Campus

Dr. B.R. Ambedkar Veedhi

Bangalore 560001

Karnataka

India

Filbert Totsingan

New York University

Department of Chemistry

100 Washington Square East

New York, NY 10003-5180

USA

Yasuhiro Tsume

University of Michigan

College of Pharmacy

Department of Pharmaceutical Sciences

428 Church Street

Ann Arbor, MI 48109

USA

Ulrika Westerlind

Gesellschaft zur Förderung der

Analytischen Wissenschaften e.V.

ISAS - Leibniz Institute of

Analytical Sciences

Otto-Hahn-Strasse 6b

44227 Dortmund

Germany

Geoffrey M. Williams

University of Auckland

Department of Chemistry

23 Symonds Street

1043 Auckland

New Zealand

Chunhui Zhou

New York University

Department of Chemistry

100 Washington Square East

New York, NY 10003-5180

USA

Zyta Ziora

The University of Queensland

Centre for Integrated Preclinical Drug

Development-Pharmaceutics

St Lucia, Brisbane, Queensland 4072

Australia

Chapter 1

Protection Reactions

Vommina V. Sureshbabu and Narasimhamurthy Narendra

1.1 General Considerations

Peptides, polypeptides, and proteins are the universal constituents of the biosphere. They are responsible for the structural and functional integrity of cells. They form the chemical basis of cellular functions that are based on highly specific molecular recognition and binding, and are involved as key participants in cellular processes. A peptide or a protein is a copolymer of α-amino acids that are covalently linked through a secondary amide bond (called a peptide bond). They differ from one another by the number and sequence of the constituent amino acids. Generally, a molecule comprised of few amino acids is called an oligopeptide and that with many amino acids is a polypeptide (molecular weight below 10 000). Proteins contain a large number of amino acids. Due to the vitality of their role for the function as well as survival of cells, peptides and proteins are continuously synthesized. Biosynthesis of proteins is genetically controlled. A protein molecule is synthesized by stepwise linking of unprotected amino acids through the cellular machinery comprised of enzymes and nucleic acids, and functioning based on precise molecular interactions and thermodynamic control. Thousands of proteins/peptides are assembled through the combination of only 20 amino acids (referred to as coded or proteinogenic amino acids). Post-translational modifications (after assembly on ribosomes) such as attachment of nonpeptide fragments, functionalization of amino acid side-chains and the peptide backbone, and cyclization reactions confer further structural diversity on peptides.

The production of peptides via isolation from biological sources or recombinant DNA technology is associated with certain limitations per se. A minor variation in the sequence of a therapeutically active peptide isolated from a microbial or animal source relative to that of the human homolog is sufficient to cause hypersensitivity in some recipients. Further, the active drug component is often not a native peptide but a synthetic analog, which may have been reduced in size or may contain additional functional groups and non-native linkages. The development of a drug from a lead peptide involves the synthesis (both by conventional and combinatorial methods) and screening of a large number of analogs. Consequently, the major proportion of the demand for peptides is still met by chemical synthesis. Chemical synthesis is also crucial for synthesizing peptides with unnatural amino acids as well as peptide mimics, which by virtue of the presence of non-native linkages are inaccessible through ribosomal synthesis.

Synthetic peptides have to be chemically as well as optically homogenous to be able to exhibit the expected biological activity. This is typically addressed by using reactions that furnish high yields, give no or minimum side-products, and do not cause stereomutation. In addition, the peptide of interest has to be scrupulously purified after synthesis to achieve the expected level of homogeneity. The general approach to synthesize a peptide is stepwise linking of amino acids until the desired sequence is reached. However, the actual synthesis is not as simple as the approach appears to be due to the multifunctional nature of the amino acids. Typically, a proteinogenic amino acid (except Gly) contains a chiral carbon atom to which is attached the amino (α-amino), carboxy, and alkyl group (referred to as the side-chain). Gly lacks the alkyl substitution at the α-carbon atom. Also, the side-chains of many of the amino acids are functionalized.

A straightforward approach to prepare a dipeptide A–B would be to couple the carboxy-activated amino acid A with another amino acid B. However, this reaction will yield not only the expected dipeptide A–B, but also an A–A (through self-acylation) due to the competing amino group of A. The so-formed dipeptides can further react with A since they bear free amino groups and form oligopeptides A–A–B, A–A–A, or A–A–A–A, and the reaction proceeds uncontrollably to generate a mixture of self-condensation products (homopolymers) and oligopeptides of the type AnB. The process becomes even more complicated when reactive functional groups are present in the side-chains of the reacting amino acid(s). The uncontrolled reactivity of multiple groups leads to the formation of a complex mixture from which it becomes a Sisyphean task to isolate the desired product, which would have been formed, mostly, in low yield. The solution to carry out peptide synthesis in a chemoselective way is to mask the reactivity of the groups on amino acids that will not be the components of the peptide bond prior to peptide coupling step. This is done by converting the intervening functional group into an unreactive (or less reactive) form by attaching to it a new segment, referred to as a protecting group (or protection or protective function). The chemical reactions used for this purpose are known as protection reactions. The protecting groups are solely of synthetic interest and are removed whenever the functional group has to be regenerated. In other words, the protection is . In the light of the concept of protection, the steps involved in the synthesis of the above dipeptide A–B are depicted in .

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