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MEDICINAL CHEMISTRY OF BIOACTIVE NATURAL PRODUCTS
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MEDICINAL CHEMISTRY
OF BIOACTIVE
NATURAL PRODUCTS
Edited by
XIAO-TIAN LIANG
WEI-SHUO FANG
Chinese Academy of Medical Sciences Beijing, China
A JOHN WILEY & SONS, INC., PUBLICATION
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Copyright # 2006 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
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Library of Congress Cataloging-in-Publication Data:
Medicinal chemistry of bioactive natural products / [edited by] Xiao-Tian Liang, Wei-Shuo Fang.
p. cm.
Includes index.
ISBN-13 978-0-471-66007-1 (cloth)
ISBN-10 0-471-66007-8 (cloth)
1. Materia medica, Vegetable. 2. Pharmaceutical chemistry. 3. Natural products. 4. Bioactive
compounds. I. Liang, Xiaotian. II. Fang, Wei-Shuo
RS431.M37M43 2006
615 0
2006000882
Printed in the United States of America
10987654321
.321 - - dc22
CONTENTS
Preface
xiii
Contributors
xvii
1 The Chemistry and Biology of Epothilones—Lead Structures
for the Discovery of Improved Microtubule Inhibitors
1
Karl-Heinz Altmann
1.1. Introduction
1
1.2. Biological Effects of Epo B
4
1.2.1 In Vitro Activity
4
1.2.2 In Vivo Antitumor Activity
8
1.3. Epothilone Analogs and SAR Studies
9
1.3.1 Lactam-Based Analogs
9
1.3.2 Modifications in the C9–C11 Region
10
1.3.3 Modifications of the Epoxide Moiety
13
1.3.4 C-26-Modified Analogs
17
1.3.5 Side-Chain Modifications
18
1.3.6 Aza-Epothilones
22
1.4. Pharmacophore Modeling and Conformational Studies
25
1.5. Epothilone Analogs in Clinical Development
26
1.6. Conclusions
28
Acknowledgments
29
References
29
v
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vi
CONTENTS
2 The Chemistry and Biology of Vancomycin and Other
Glycopeptide Antibiotic Derivatives
35
Roderich D. S¨ ssmuth
2.1. Introduction
35
2.2. Classification of Glycopeptide Antibiotics
37
2.3. Mode of Action
39
2.4. Glycopeptide Resistance
40
2.5. Biosynthesis
43
2.6. Total Synthesis
45
2.7. Glycopeptides as Chiral Selectors in Chromatography and
Capillary Electrophoresis
47
2.8. Structural Modifications of Glycopeptide Antibiotics and
Structure Activity Relationship (SAR) Studies
49
2.8.1 Modifications of Glycopeptide Antibiotics
51
2.8.2 Rational Concepts for the Design of Novel Glycopeptides
58
2.8.3 Conclusions
64
Acknowledgment
65
References
65
3 Structure Modifications and Their Influences on Antitumor
and Other Related Activities of Taxol and Its Analogs
73
Wei-Shuo Fang, Qi-Cheng Fang, and Xiao-Tian Liang
3.1. Discovery and Research and Development of Taxol
73
3.2. Paclitaxel Analogs Active Against Normal Tumor Cells
74
3.2.1 C-13 Side Chain
74
3.2.2 A Ring and Its Substitutions
81
3.2.3 B Ring and Its Substitutions
87
3.2.4 C Ring and Its Substitutions
94
3.2.5 D Ring
101
3.2.6 Macrocyclic Analogs
103
3.2.7 Miscellaneous
104
3.3. Exploration on Mechanism of Paclitaxel Related to Tubulin
Binding and Quest for Its Pharmacophore
106
3.3.1 Biochemical Mechanism of Paclitaxel Related
to Tubulin Binding
106
3.3.2 Identification of Bioactive Conformations and Quest
for a Pharmacophore for Paclitaxel
108
3.4. Natural and Semisynthetic Taxoids Overcoming Multidrug
Resistance (MDR)
111
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