AlkaloidsBiochemistry, Ecology, andMedicinal Applications

AlkaloidsBiochemistry, Ecology, andMedicinal Applications

Edited by

Margaret F. RobertsThe University of LondonLondon, England

and

Michael WinkUniversity of HeidelbergHeidelberg , Germany

Springer Science+Business Media, LLC

Library of Congress Cataloging-in-Publication Data

Alkaloids biochemistry. ecology. and medicinal applications I edited by Margaret F. Roberts and Michael Hink.

p. em. Includes bibliographical references and index.

1. Alkaloids. Michael. QP801.A34A44 1998 572' .549-·-dc21

I. Roberts. M. F. (Margaret F.) II. Hink.

ISBN 978-1-4419-3263-1 ISBN 978-1-4757-2905-4 (eBook) DOI 10.1007/978-1-4757-2905-4

© 1998 Springer Science+Business Media New York Originally published by Plenum Press, New York 1998. Softcover reprint of the hardcover 1 st edition 1998

http://www.plenum.com

1098765432 1

All rights reserved

98-17602 CIP

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

Contributors

J. C. Braekman • Laboratory of Bio-Organic Chemistry, Free University of Brussels,50-1050 Brussels, Belgium

D. Daloze • Laboratory of Bio-Organic Chemistry, Free University of Brussels, 50-1050Brussels, Belgium

Rainer Ebel • Julius von Sachs Institute for Biological Sciences, Department of Phar­maceutical Biology, University of Wtirzburg, D-97082 Wiirzburg, Germany

U. Eilert • Institute for Pharmaceutical Biology, Technical University of Braun­schweig, D-38106 Braunschweig, Germany

A. H. C. Hoult • Department of Agronomy and Soil Science, University of NewEngland, Armidale, NSW 2351, Australia

J. V. Lovett • Grains Research and Development Corporation, Kingston, ACT 2604,Australia

Isamu Murakoshi • Faculty of Pharmaceutical Sciences, Laboratory of Molecular Bi­ology and Biotechnology , Research Center of Medicinal Resources, Chiba Univer­sity, Inage-ku, Chiba 263, Japan

H. D. Neuwinger • Department of Chemistry, University of Heidelberg, D-69120Heidelberg, Germany (Retired). Present address: Hauptstrasse 190, D-68789 St.Leon-Rot, Germany

J. M. Pasteels • Laboratory of Animal and Cellular Biology, Free University of Brus­sels, 50-1050 Brussels, Belgium

Peter Proksch • Julius von Sachs Institute for Biological Sciences, Department ofPharmaceutical Biology, University of Wtirzburg, D-97082 Wtirzburg, Germany

Margaret F. Roberts • The Centre for Pharmacognosy , School of Pharmacy, Universityof London, London WCIN lAX, England

Richard J. Robins • Laboratoire d' Analyse Isotopique et Electrochimique de Metabo­lismes, CNRS UPRES-A 6006, University of Nantes, BP 92208, F-44322 NantesCedex 03, France

v

vi Contributors

Kazuki Saito • Faculty of Pharmaceutical Sciences, Laboratory of Molecular Biologyand Biotechnology, Research Center of Medicinal Resources, Chiba University,Inage-ku, Chiba 263, Japan

T. Schmeller • Institute for Pharmaceutical Biology, University of Heidelberg, D-69l20Heidelberg, Germany

F. R. Stermitz • Department of Chemistry , Colorado State University, Fort Collins,Colorado 80523

R. Verpoorte • Division of Pharmacognosy, LeidenlAmsterdam Center for Drug Re­search, University of Leiden, 2300 RA Leiden, The Netherlands

Peter G. Waterman • Phytochemistry Research Laboratories , University of Strath­clyde, Glasgow G1 lXW, Scotland

Michael Wink • Institute for Pharmaceutical Biology, University of Heidelberg,D-69120 Heidelerg, Germany

Preface

We have tried, in this book, to provide a survey of recent scientific thinking on the biologyof that heterogenous group of secondary metabolites, the alkaloids. To this end, we haveprevailed on scientists who are specialists in their particular areas to define the currentthinking in their areas of expertise. G. R. Waller and E. K. Nowacki edited AlkaloidBiology and Metabolism in Plants in 1978. The present volume can be regarded as asequel.

The book is designed for use by advanced students and professional workers in theagricultural, biological, and pharmaceutical sciences, natural products chemistry, bio­chemistry, and botany. Each chapter is referenced with its own set of review and specialistreferences. Chapters are arranged in four parts: Part I is an introduction covering some of thehistorical uses of alkaloids; Part II considers the biochemistry of alkaloid production inplants; Part III discusses ecology and includes marine invertebrates, animals, and plantparasites; and Part IV studies alkaloids as antimicrobials and reviews the current medicinaluse. The volume is an attempt to put into one book current thoughts in these areas and assuch cannot be exhau stive on such a large and diverse group of constituents. For otherdetails the reader should consult such reviews as The Alkaloids, first edited by R. H.Manske, later by A. Brossi and G. A. Cordell, 1952-1996, Academic Press, New York;Alkaloids: Chemical and Biological Perspectives, edited by S. W. Pelletier, 1983-1996,Pergamon Press, Oxford; and The Chemical Society Specialist Reports on Natural Products .

This book has brought together contributions from friends and colleagues from manyparts of the world. As editors, we would like to thank all those who have taken part in thewriting and preparation of this book.

M. F. ROBERTS

M. WINK

vii

Contents

Chapter 1

Introduction

Margaret F. Roberts and Michael Wink

1. Introduction. . . . . . . .. . . . .. . ... . . . .. .. ... . . .. .. . . .. . ..... . . . . .... .. 12. Historical Importance of Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. Biochemistry. .. . . . . . . .. . .. . . .. .. .... . . ... .. .... ... . . . .... . . ... . .. 2

3.1. Classification of Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2. Biogenetic Grouping of Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.3. Occurrence and Distribution . . . . . . . . . . . . . . . . . . . . . . . 3

4. Ecology.. . .. .. .... .. .. . . . . .. .. . .. .. .. .... . . .. ... . . .. .. ... . .. ... . 45. Pharmacological Activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Part I. Historical and Cultural Perspectives

Chapter 2

A Short History of Alkaloids

Michael Wink

1. Introduction. . .. .. . . . .. . . .. . .. . . . .. . . ...... . . ....... ... . ..... .. .. . 112. Alkaloids and Alkaloid-Producing Plants in Antiquity. . . . . . . . . . . . . . . . . . . . 12

2.1. Use of Alkaloid-Producing Plants in Early Medicine. . . . . . . . . . . . . . . . 122.2. Role of Alkaloids and Alkaloidal Plants for "Murder" and "Magic" . . . 14

3. Alkaloidal Plants and Fungi Playing an Important Rolein the History of Mankind. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173.1. Aconitum napellus (Family Ranunculacaea) . . . . . . . . . . . . . . . . . . . . . . . 173.2. Amanita muscaria (Family Amanitaceae) . . . . . . . . . . . . . . . . . . . . . . . . . 183.3. Areca catechu (Family Arecaceae) .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193.4. Aristolochia clematitis (Family Aristolochiaceae) 193.5. Atropa belladonna (Family Solanaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . 20

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3.6. Banisteriopsis caapa, B. inebrians (Family Malpighiaceae) ... . . . . . . . 223.7. Buxus sempervirens (Family Buxaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . 223.8. Camellia sinensis (Family Theaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233.9. Chelidonium majus (Family Papaveraceae). . . . . . . . . . . . . . . . . . . . . . . . 243.10. Claviceps purpurea (Family Hypocreaceae) . . . . . . . . . . . . . . . . . . . . . . . 253.11. Colchicum autumnale (Family Liliaceae) . . . . . . . . . . . . . . . . . . . . . . . . . 263.12. Conium maculatum (Family Umbelliferae) ..... .. .... ....... . . ... . 273.13. Datura metel (Family Solanaceae) 283.14. Delphinium consolida (Family Ranunculaceae) . . . . . . . . . . . . . . . . . . . . 283.15. Dictamnus albus (Family Rutaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293.16. Ephedrafragilis (Family Ephedraceae). .. . . . . 293.17. Erythroxylum coca (Family Erythroxylaceae).. ... .......... ... .... 303.18. Hyoscyamus niger, H. albus, H. muticus (Family Solanaceae) . . . . . . . . 313.19. Lophophora williamsii (Family Cactaceae).. . . ... . 323.20. Lupinus albus (Family Leguminosae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323.21. Lycopodium clavatum, L annotinum (Family Lycopodiaceae) . . . . . . . . 333.22. Mandragora officinarum, M. autumnalis (Family Solanaceae) . . . . . . . . 343.23. Nicotiana tabacum (Family Solanaceae). . . . . . . . . . . . . . . . . . . . . . . . . . 353.24. Papaver somniferum (Family Papaveraceae) 353.25. Peganum harmala (Family Zygophyllaceae) 373.26. Physostigma venenosum (Family Leguminosae). . . . . . . . . . . . . . . . . . . . 383.27. Psilocybe mexicana (Family Agaricaceae) . . . . . . . . . . . . . . . . . . . . . . . . 383.28. Punica granatum (Family Punicaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . . 393.29. Ruta graveolens (Family Rutaceae). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403.30. Solanum dulcamara (Family Solanaceae) . . . . . . . . . . . . . . . . . . . . . . . . . 403.31. Taxus baccata (Family Taxaceae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413.32. Turbina corymbosa (Family Convolvulaceae). . . . . . . . . . . . . . . . . . . . . . 423.33. Veratrum album (Family Liliaceae). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Major Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Chapter 3

Alkaloids in Arrow Poisons

H. D. Neuwinger

1. Introduction .. ...... ... .. .. .. ....... . ... .. .. ... .... . .... .. ..... .. . 452. African Arrow Poisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

2.1. Poisoned Weapons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472.2. Poison Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492.3. Plant Sources and Their Active Principles . . . . . . . . . . . . . . . . . . . . . . . . 50

3. South American Arrow Poisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713.1. Classification and Composition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723.2. Chemistry. .. .. ..... .. ..... .. . . . .. . . . . . ... ..... .. . . . ........ 733.3. Pharmacology, Toxicology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743.4. Medicinal Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Content s xi

3.5. Other Plant Arrow Poisons 764. Asian Arrow Poisons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

4.1. Indonesia, Borneo, Philippines, Hainan, Vietnam, Cambodia . . . . . . . . . 784.2. Burma. Thailand, Malaysia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Appendix: Composition of African Arrow Poisons . . . . . . . . . . . . . . . . . . . . . . 81References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

General References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Specific References 83

Part II. Biochemistry

Chapter 4

Chemical Taxonomy of Alkaloids

Peter G. Waterman

1. Introduction... . . .... . . .. .. ... . . ... . . ... . . . .. .. . .... . . ....... . . ... 872. What Is an Alkaloid? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

2.1. A Unifying Theme in the Biosynthesis of True Alkaloids. . . . . . . . . . . . 883. The Impact of Alkaloids on Taxonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

3.1. Alkaloids Originating from Tyrosine (and Phenylalanine),UsualIy through Dopa 90

3.2. Indole-seco-Loganin-Derived Alkaloids : . . . . . . . . 963.3. Anthranilic Acid as an Alkaloid Substrate . . . . . . . . . . . . . . . . . . . . . . . . 983.4. Alkaloids from Ornithine and Lysine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003.5. Pseudoalkaloids. .. .. . .. . . .. . .. ... .. .. ........ .. .... . . .. . ... .. 104

4. Concluding Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105Key References... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 106

Chapter 5

Enzymology of Alkaloid Biosynthesis

Margaret F. Roberts

I. Introduction . . . . . . . .... . . . .. .... . .. . .. .. ..... ..... . . .. ... .. . .... .. 1092. Biosynthesis of Acetate-Derived Simple Piperidine Alkaloids. . . . . . . . . . . . . 1103. Biosynthesis of Quinolizidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1124. Biosynthesis of Benzylisoquinoline Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . 114

4.1. The Formation of (S)-Norcoclaurine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144.2. Biosynthesis of the Tetrahydroberberine Alkaloids. . . . . . . . . . . . . . . . . . 1164.3. The Route to the Protopine and Benzophenanthridine Alkaloids 1184.4. Biosynthesis of the Morphinan Alkaloids : . . . . . . . . . . . . 120

5. Indole Alkaloid Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1215.1. Formation of (S) -Strictosidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

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5.2. Deglucosylation of Strictosidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255.3. Formation of Corynanthe-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . 1255.4. The Formation of Sarpagan-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . 1255.5. Formation of Aspidosperma-Type Alkaloids. . . . . . . . . . . . . . . . . . . . . .. 1305.6. Biosynthesis of Dimeric Indole Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . 132

6. Ergot Alkaloid Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1327. Cyclopenin-Viridicatin Alkaloid Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . .. 1378. Acridone Alkaloid Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1399. Conclusions. .. . . .. . . . . . . .. . . . . . . . . . . . . . ... . . .. .. . . ........ . . . ... . 139

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 140General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 140Key References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 141

Chapter 6

Genes in Alkaloid Metabolism

Kazuki Saito and Isamu Murakoshi

1. Introduction.. .. ...... .. .. . . . .... . . . . . .... .. . . . . . ... . . .. .. .. . . . .. . 1472. Isolation of Genes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1473. Regulation. .. ...... .. . . . . ... . . .. ....... ... . . . . . . . . . . . . . . . . . . . . . . . 1494. Expression of Recombinant Enzymes in Heterologous Systems. . . . . . . . . . . . 150

4.1. Expression in Microorganisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ISO4.2. Expression in Transgenic Plants and Other Higher Organisms . . . . . . . . 153

5. Molecular Evolution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1536. Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 155General Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Key References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Chapter 7

Production of Alkaloids in Plant Cell Culture

Margaret F. Roberts

I. Introduction. . . . .. .. ...... ... . . . . ....... ..... .. . . .. . .... .... .. . . . . 1592. Cell Technology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 161

2.1. Cell Culture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612.2. Establishment of Specific Cell Lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642.3. Growth and Product Accumulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1662.4. Development of Cultures with Improved Alkaloid Yield. . . . . . . . . . . . . 1672.5. Immobilization of Plant Cells and Enzymes . . . . . . . . . . . . . . . . . . . . . . . 1692.6. Organ Culture ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.7. Plant Propagation by Tissue Culture Techniques . . . . . . . . . . . . . . . . . . . 1722.8. Cell Cultures for the Production of Alkaloids 1732.9. Lysine-Derived Quinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . 184

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2.10. Ornithine-Derived Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1842.11. Nicotinic Acid-Derived and Purine Alkaloids. . .. . .... . . .... . . . . . .. 1862.12. Anthranilic Acid-Derived Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1872.13. Acetate-Derived Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

3. Industrial Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1893.1. The Problem of Cost-Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1893.2. The Problems Associated with Scaleup. . . . . . . . . . . . . . . . . . . . . . . . . .. 1903.3. Areas of Potential Industrial Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

4. Summary . ... ... ...... ..... .... . . . . . . . .. . .. ...... ... ....... ... . .. 192References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 192

General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 192Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Chapter 8

The Biosynthesis of Alkaloids in Root Cultures

Richard J. Robins

1. Introduction... . . ... . .. ... . .... .. .. . . .... . .. . . . . .... . .. . . . . . . . . . . . 1992. The Pyrrolidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 200

2.1. Regulation of the Pyrrolidine Alkaloid Pathway in Nicotiana. . . . . . . . . 2022.2. Studying the Pyrrolidine Alkaloid Pathway by Genetic Engineering . . . 203

3. The Tropane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2053.1. The Biosynthetic Route to the Tropane Alkaloids . . . . . . . . . . . . . . . . .. 2063.2. Regulation of the Tropane Alkaloid Pathway

in Datura, Hyoscyamus, and Atropa . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2063.3. Genetic Engineering of Tropane Alkaloid Biosynthesis. . . . . . . . . . . . . . 211

4. The Pyrrolizidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2124.1. The Biosynthetic Route to the Pyrrolizidine Alkaloids . . . . . . . . . . . . . . 2124.2. Regulation of the Biosynthetic Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . 213

5. Conclusions . . . .... . . .. .. . ... . ... . . ........ . .. . . . .. . . . .... ... ... . . 215References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

General Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 216

Chapter 9

Induction of Alkaloid Biosynthesis and Accumulation in Plantsand in Vuro Cultures in Response to Elicitation

U. Eilert

1. Introduction. .. . . . . . .. . ... . . ... . . .... ... . .. . . . . .. . . . . . . . . .. . . .. ... 2192. Induction of Alkaloid Production by Climatic and Soil Conditions

in Field-Grown Plants 2202.1. Induction by Heat Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2202.2. Induction by Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

xiv Contents

3. Induction of Alkaloid Production in Vitro. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2224. Induction by Wounding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

4.1. Effects of Mechanical Wounding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2244.2. Elicitor Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

5. Concluding Remarks 232References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Chapter 10

Compartmentation of Alkaloid Synthesis, Transport, and Storage

Michael Wink and Margaret F. Roberts

I. Introduction .... . . ...... . . .... . ... .. . . . .. .... . .. .. . ...... . . ..... .. 2392.1. Sites and Compartmentation of Alkaloid Formation 2392.2. Long-Distance Transport. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 241

3. Alkaloid Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2423.1. Vacuolar Sequestration of Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2423.2. Mechanisms Underlying Vacuolar Sequestration . . . . . . . . . . . . . . . . . .. 244

4. Turnover of Alkaloids 2485. Sequestration as an Integral Part of the Defense Concept of Plants . . . . . . . . . 254

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Special References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 258

Part III. Ecology

Chapter 11

Chemical Ecology of Alkaloids

Michael Wink

1. Introduction. . ..... .... ....... . . . .. .... . . ... .. .. . . . .. .. .. .. ....... 2652. Function of Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2683. Plant-Herbivore Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 269

3.1. Invertebrates . .. . .. . . .. ...... .. . ..... . . .. . . ... ... .. . ... . . . .. . 2693.2. Vertebrate Herbivores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

4. Plant-Microbe Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2845. Plant-Plant Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2866. Ecological Relevance of Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 286

6.1. Are Alkaloid Concentrations in Plants Sufficiently High? . . . . . . . . . . .. 2876.2. Occurrence of Alkaloids at the Right Site and Right Time . . . . . . . . . . . 2896.3. Evidence for Alkaloid-Mediated Fitness . . . . . . . . . . . . . . . . . . . . . . . . . . 292

7. Conclusion. . .. .... .. . . . .... . . .... . . . . . .... .. . .. . . . .. . . . ... . . .. . . 296

Contents xv

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297Major Reviews " 297Key References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

Chapter 12

Modes of Action of Alkaloids

Michael Wink

1. Introduction... . . . . . .. . . .. .. .. ... . . .... ..... .... .. . . .. . . . . . ...... . 3012. Molecular Targets of Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

2.1. Biomembranes... ........ . .. .... .... . .. . . ... . .. .. ...... . . ... 3022.2. Signal Transduction at Biomembranes 3022.3. Cytoskeleton . ...... ....... .. ... . .... ... . ....... ....... ..... . 3092.4. DNA/RNA .. . . . .. .. .. . .. .. . ... .. .... . ... . ... .... . . . . . . . . . .. 3122.5. Protein Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3142.6. Electron Chains " ' " . 3162.7. Modulation of Enzyme Activity through Alkaloids . . . . . . . . . . . . . . . .. 3162.8. Alkaloids Affecting More than One Target. . . . . . . . . . . . . . . . . . . . . . .. 316

3. Targets at the Organ Level. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3203.1. Central Nervous System and Neuromuscular Junction " 3203.2. Inhibition of the Digestive Process. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3223.3. Modulation of Liver and Kidney Function. . . . . . . . . . . . . . . . . . . . . . . . 3233.4. Disturbance of Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3233.5. Blood and Circulatory System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3243.6. Allergenic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

4. Mechanisms of Allelochemical Activities in Antiviral, Antimicrobial,and Allelopathic Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

5. Conclusions.. . . . ....... . ... . .. . . . . .... . .... . .. .... . . .... .... . .. . . 324References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 325

Major Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325Key References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 325

Chapter 13

Plant Parasites

F. R. Stermit;

1. Introduction. .. ... . . ....... .. ... ........ .... . . . . . .. . .. . . .. . . . ..... 3272. Specificity . ... . .... . . .... . . . . .. . . . .. . .. .. .. . .. . . . . .. .. . .. .. . ... . . 328

2.1 Host Plant Specificity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3282.2 Specificity of Alkaloid Uptake: Root Parasites. . . . . . . . . . . . . . . . . . . . . 3302.3 Specificity of Alkaloid Uptake: Stem Parasites . . . . . . . . . . . . . . . . . . .. 330

3. Ecological Aspects of Alkaloid Transfer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

xvi Contents

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 335General References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Specific References 335

Chapter 14

AUelopathy in Plants

J. V. Lovett and A. H. C. Boult

1. Introduction... .......... ..... . . .. ....................... ...... . .. 3372. Allelopathic Activity of the Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339

2.1. Against Mircoorganisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3392.2. Against Higher Plants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

3. The Significance of Alkaloid-Mediated Allelopathy in Ecosystems . . . . . . . . . 3423.1. Criteria for Establishing Allelopathic Activity in Ecosystems. . . . . . . .. 3423.2. Soil Mediation 3423.3. Other Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

4. Conclusion .... .. . ......... . ... . . . .. ..... ............. ....... .... 344References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 345

General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 345Specific References 346

Chapter 15

Alkaloids in Animals

J. C. Braekman, D. Daloze, and J. M. Pasteels

1. Introduction... . ... . ...... .......... . ......... .. . .......... ...... . 3492. Arthropods... ............... ... .... .... ... .. . ... . ... ... . . . . ... .. 350

2.1. Insecta.. ..... . ... .. ... .. .............. ..... .. ....... ... .... 3502.2. Arachnida..... . ........ ... . . .. . ..... . ... ..... . .. .. . . . . ... .. 3612.3. Myriapoda-Diplopoda. .... ........... ... ... .......... ..... . .. 363

3. Vertebrates. ........ . . .... .. . ... .......... ...................... .. 3643.1. Amphibia.. ... . . .. ......... . . . ... .... . .. . .. . .. . .... . . . .. .... 3643.2. Other Vertebrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

4. Marine Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3674.1. Bryozoa (Ectoprocta or Moss Animals) . . . . . . . . . . . . . . . . . . . . . . . . .. 3694.2. Tunicates (Ascidians) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3694.3. Porifera. .. .... . ..... . . .. ........ ... .. ... . ....... ......... .. 372

5. Biosynthesis. ... .. ... . ...... ....... ........ . . .. . ... .... ..... ..... 372References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 373

General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 373Specialist References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

Chapter 16

Ecological Significance of Alkaloids from Marine Invertebrates

Peter Proksch and Rainer Ebel

1. Introduction. .. . .. ...... . . .. ......... ........ ... ... . . . .. . . ... .. .. . 379

Contents xvii

2. Chemical Defense against Fouling and Spatial Competition. . . . . . . . . . . . . .. 3803. Chemical Defense against Fish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3834. Induced Chemical Defense of the Sponge Verongia aerophoba . . . . . . . . . . . . 3855. Marine Alkaloids as Waterborne Signals in Inter- and

Intraspecific Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3886. Origin of Alkaloids from Marine Invertebrates 3897. Chemical Defense in the Marine versus the Terrestrial Environment . . . . . . . . 390

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 391General Reviews. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 391Specific References 392

Part IV. Alkaloids in Medicine

Chapter 17

AntimicrobialJy Active Alkaloids

R. Verpoorte

1. Introduction . . . ... . . . .. . . .. . . . .. . . . . . . ...... . .. . .. ... . . .. .. . . . .. .. 3972. Indole Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

2.1. Terpenoid Indole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3982.2. Other Indole Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404

3. Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4053.1. Bisbenzylisoquinoline Alkaloids. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 4103.2. Aporphine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4113.3. Benzophenanthridine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4133.4. Protoberberine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4143.5. Protopines . . . . . . .. . . . . . ..... . . . . . . . . . . .. . . . . . . . . . ... .. .. . . . . 4163.6. Miscellaneous Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416

4. Steroidal Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4165. Quinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4216. Acridone Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 4217. Terpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4228. Piperidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4229. Quinolizidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42310. Pyrrolizidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 42311. Miscellaneous . . . . .. . . .. . . . . . . . . . .. . . . . . . . . . .. . . . . . . . .. . . . .. . . . . . . 42312. Conclusion .. . . . . ... . . . . .. . .. . . . . . . . . .. . .. ... . . . . . . .. . ..... .. . . . . 424

References ' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425General Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 425Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 426

Chapter 18

Utilization of Alkaloids in Modern Medicine

T. Schmeller and Michael Wink

1. Introduction. .. .. .. .... .. . . . .... . . ... . . .. . . ..... .... . . . . . . . . .. .. . . 435

xviii Contents

2. Alkaloids Used in Modem Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4362.1. Aconitine.. . . . . . . . . . . . . . . . . . . ... ... .. .. .. ...... . . . . . . . . . . ... 4362.2. Ajmaline .. .. . . ..... . . . ..... . ... ... . . . ... . . . . . .. . .. ...... ... 4362.3. Atropine . ... . . . . . .... . . . . . . ..... . .. . ....... ....... . .... . . .. 4372.4. Berberine..... . .. ...... . .. ..... ... ... . . . ... . . . ... . . .. .... . . . 4382.5. Boldine . . . . . . .. . . . . . . . . .. . . . .. ... .... . ..... .. ..... ..... . . .. 4382.6. Caffeine. ...... . . . ...... . . . .... . .. .. . . . . . .. . . . ..... . . .... . . . 4392.7. Cathine.. . . . . ..... . . . ... . . . .... ... .... .. ..... . . . . . . . . . .... . 4392.8. Cocaine...... ....... ... .... ..... . ... . . . . . . . . . . ... ...... .... 4402.9. Codeine. . .. . . . . .... . . . . . . . . .... ....... ........ . . . . . . . . ..... 4402.10. Colchicine...... . ..... .... .. . . .. ... . ..... ....... ...... . ... . . 4412.11. Emetine . ... . . . . . . .... . . .. . . ..... ... . . . . . . . . ... . . . . . . . . ..... 4412.12. Ephedrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4422.13. Ergometrine... . . . . . .... . . . . ... ... ... . .... ....... .. ....... . . . 4432.14. Ergotamine . ..... . .. .......... . ...... . . . . . . . ..... . . . . . . ..... 4432.15. Eserine (= Physostigmine) 4442.16. Galanthamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4442.17. Hydrastine. . . ..... .. .. .. . ..... . . ... .. . . . . . . . ... . . . . . . ... . . . . 4452.18. Hyoscine (= Scopolamine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4452.19. Hyoscyamine. . . . ... . . . ... . . . . . .. . .. . . . . . . . . . . . . . . . . ......... 4462.20. Lobeline 4462.21. Morphine.... . . . . . ... . . .. . . ..... .... . .. . . .... . . . . . ...... . . . . 4462.22. Narceine... ... .. .... . ..... . ..... ... . ... . . ... . . . . . . ... . . .. . . 4472.23. Nicotine. . . ... . . . . . . .... .. . . . .... . .. . .. . . . . . . . . . . . . .. . ...... 4472.24. Noscapine (= Narcotine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4482.25. Papaverine... . . . . . ......... . . . .... . . .. .... ....... . . . . ..... . . 4482.26. Physostigmine (see Eserine). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4492.27. Pilocarpine . . . . . . .. ..... ... . ............ .. . .. .... ....... .... 4492.28. Quinidine. ...... . . ..... . . . .. . . . ... . .. . . . . . . . .... . . ..... . .... 4492.29. Quinine.. . . ..... .. ..... . . . .. ...... .... . .... ...... . .. . . ..... 4502.30. Raubasine ( = Ajmalicine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4502.31. Rescinnamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4512.32. Reserpine. . . . .. . ... ..... . ... ...... . .... . .. . . .... . ..... . . .... 4512.33. Sanguinarine.. . . . ..... . . . .. . . . ..... .... . .... .... . . ..... . . . . . 4522.34. Scopolamine (see Hyoscine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4532.35. Sparteine. . ... .. . . . . ....... . .. ........ . .. . .. ... . . . .. . . .. . . . . 4532.36. Strychnine. .. . . ..... .. .. . . . .... . . . . . ...... . ..... . ....... . . .. 4532.37. Taxol . . . ... . . . . ...... . .. ... . . ...... ... . . . . ..... . . . . . ... . . . . 4542.38. Theobromine . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4542.39. Theophylline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4552.40. Tubocurarine . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 4552.41. Vinblastine 4562.42. Vincamine . . . . . . .... . . ..... . . .. .... . ... . . .... . . ... . . ..... .. . 4572.43. Vincristine ... . ... . . . ...... . . . ... . . . . . .. ..... . . . .. . . . . . . ... . . 4572.44. yohimbine ... .. . ... . . . . . ... . . .. . . ... .. . . ... ... . .... .. .. ..... 457

3. Conclusions.. . . .. . . . . .... .. .. ... .. ..... . . .... .. .... ...... . . . ..... 458References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 458

Contents xix

Subject Index Including Orders, Families, and Common Names. . . . . . . . . . . . 461

Index of Alkaloids, Amines, and Other Molecules . . . . . . . . . . . . . . . . . . . . . . . 469

Organism Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479

AlkaloidsBiochemistry, Ecology, andMedicinal Applications