ALKALOIDS – SECRETS OF LIFE ALKALOID CHEMISTRY, BIOLOGICAL SIGNIFICANCE, APPLICATIONS AND ECOLOGICAL ROLE This page intentionally left blank ALKALOIDS – SECRETS OF LIFE ALKALOID CHEMISTRY, BIOLOGICAL SIGNIFICANCE, APPLICATIONS AND ECOLOGICAL ROLE Tadeusz Aniszewski Associate Professor in Applied Botany Senior Lecturer Research and Teaching Laboratory of Applied Botany Faculty of Biosciences University of Joensuu Joensuu Finland Amsterdam • Boston • Heidelberg • London • New York • Oxford • Paris San Diego • San Francisco • Singapore • Sydney • Tokyo Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2007 Copyright © 2007 Elsevier B.V. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13: 978-0-444-52736-3 ISBN-10: 0-444-52736-2 For information on all Elsevier publications visit our website at books.elsevier.com Printed and bound in The Netherlands 070809101110987654321 Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org Dedicated to my Family and Friends This page intentionally left blank Contents List of Figures xi List of Tables xv Preface xvii Chapter 1 Definition, Typology and Occurrence of Alkaloids 1 1. Definition 1 1.1. True alkaloids 6 1.2. Protoalkaloids 6 1.3. Pseudoalkaloids 11 2. Occurrence in nature 12 2.1. The Dogbane botanical family (Apocynaceae) 13 2.2. The Aster botanical family (Asteraceae) 17 2.3. The Logan botanical family (Loganiaceae) 19 2.4. The Poppy botanical family (Papaveraceae) 21 2.5. The Citrus botanical family (Rutaceae) 22 2.6. The Nightshade botanical family (Solanaceae) 25 2.7. The Coca botanical family (Erythroxylaceae) 27 2.8. The Borage botanical family (Boraginaceae) 28 2.9. The Legume botanical family (Fabaceae) 29 2.10. The Monseed botanical family (Menispermaceae) 45 2.11. The Berberry botanical family (Berberidaceae) 46 2.12. The Buttercup botanical family (Ranunculaceae) 47 2.13. The Lily botanical family (Liliaceae) 48 2.14. The Coffee botanical family (Rubiaceae) 49 2.15. The Amaryllis botanical family (Amaryllidaceae) 51 2.16. The Oleaster botanical family (Elaeagnaceae) 53 2.17. The Caltrop botanical family (Zygophyllaceae) 53 2.18. Mushroom 54 2.19. Moss 55 2.20. Fungus and bacter 55 2.21. Animals 57 Chapter 2 Alkaloid Chemistry 61 1. Alkaloids as secondary metabolism molecules 61 2. Synthesis and metabolism 66 2.1. Skeleton diversity 67 2.2. Ornithine-derived alkaloids 73 viii Contents 2.3. Tyrosine-derived alkaloids 76 2.3.1. Mescaline pathway 76 2.3.2. Kreysigine and colchicine pathway 77 2.3.3. Dopamine – cephaeline pathway 78 2.3.4. Galanthamine pathway 78 2.4. Tryptophan-derived alkaloids 78 2.4.1. Psilocybin pathway 79 2.4.2. Elaeagnine, harman and harmine pathway 80 2.4.3. Ajmalicine, tabersonine and catharanthine pathway 81 2.4.4. Vindoline, vinblastine and vincristine pathway 81 2.4.5. Strychnine and brucine pathway 83 2.4.6. Quinine, quinidine and cinchonine synthesis pathway 83 2.4.7. Eserine synthesis pathway 84 2.4.8. Ergotamine synthesis pathway 84 2.5. Nicotinic acid-derived alkaloids 85 2.6. Lysine-derived alkaloids 87 2.6.1. Pelletierine, lobelanine and piperine synthesis pathway 87 2.6.2. The swansonine and castanospermine synthesis pathway 88 2.6.3. The lupinine, lupanine, sparteine and cytisine synthesis pathway 88 2.7. Methods of analysis 90 2.7.1. Methodological considerations 91 2.7.2 Structural approach 95 2.7.2.1. Piperidine alkaloids 95 2.7.2.2. Indolizidine alkaloids 96 2.7.2.3. Quinolizidine alkaloids 98 2.7.2.4. Pyrrolizidine alkaloids 101 2.7.2.5. Izidine alkaloids 103 2.7.2.6. Pyrrolidine alkaloids 103 2.7.2.7. Tropane alkaloids 103 2.7.2.8. Imidazole alkaloids 104 2.7.2.9. Quinazoline alkaloids 105 2.7.2.10. Acridone alkaloids 106 2.7.2.11. Pyridine alkaloids 107 2.7.2.12. Sesquiterpene pyridine alkaloids 107 2.7.2.13. Phenyl and phenylpropyl alkaloids 110 2.7.2.14. Indole alkaloids 111 2.7.2.15. Manzamine alkaloids 119 2.8. Biogenesis of alkaloids 122 2.8.1. Chemistry models 122 2.8.2. Biochemistry models 124 2.8.3. Molecular biology models 126 2.8.4. Analytical dilemmas 127 2.9. Methods of alkaloid analysis 128 2.9.1. Methods in history 129 2.9.2. Basic methods and instruments 129 2.9.3. From iodine to enzyme 129 Contents ix 2.9.4. Choice of method and confidence 136 2.9.5. Chemical modification of alkaloids 138 Chapter 3 Biological Significance of Alkaloids 141 1. Alkaloids in biology 141 1.1. From stimulators to inhibitors and destroyers of growth 143 1.2. The effects of stress and endogenous security mechanisms 146 2. Bioactivity 148 2.1. Secrets of life 148 2.2. Life regulation through the high and low cytotoxicity 150 2.3. Haemoglobinization of leukaemia cells 153 2.4. Estrogenic effects 155 2.5. Antimicrobial properties 156 2.6. Anti-parasitic activity 158 3. Biotoxicity 161 3.1. Research evidence 161 3.2. Influence on DNA 162 3.3. Selective effectors of death 163 3.4. Non-toxic to self but deformer for others 164 3.5. Degenerators of cells 166 3.6. Aberrations in cells 167 3.7. Causers of locoism 168 4. Narcotics 169 5. Alkaloids in the immune system 172 6. Genetic approach to alkaloids 175 7. Alkaloids in the evolution of organisms 178 Chapter 4 Applications 181 1. Medicinal applications 182 1.1. Regulation of Na+ ions and channels 184 1.2. Regulation of mescarinic cholinergic receptor 185 1.3. Regulation of acetylcholine esterase 185 1.4. Regulation of opioid and opiate receptors 186 1.5. Regulation of glycine receptors 186 1.6. Regulation of other receptors 186 1.7. Regulation of microtubules of the spindle apparatus 187 1.8. Regulation of microbial activity 187 1.9. Regulation of stimulation 187 1.10. Regulation of schizonticide activity 188 2. Alkaloids as drugs 188 3. Agricultural applications 191 3.1. Alkaloids in food 192 3.2. Alkaloids as biological fertilizers 194 3.3. Alkaloids in plant protection 195 x Contents 4. Biotechnology 197 4.1. Cell cultures 198 4.2. Root cultures 203 Chapter 5 The Ecological Role of Alkaloids 205 1. Animal sequestration of alkaloids 206 2. Sexual behaviour 212 3. Feeding attraction and deterrence 213 4. A case study: Alkaloids and population changes 214 4.1. Introduction 214 4.2. Material and methods 215 4.2.1. Method of QAs+ indications 217 4.2.2. Mutational trajectories 218 4.3 Results 219 4.3.1. QAs+ occurrence and frequency 219 4.3.2. Tendencies of QAs+ plants to evolve and their MECs 219 4.3.3. Tendencies and dependencies of species 227 4.4. Discussion of case study results 231 Appendix Alkaloid Extraction Protocol 235 References 237 Indices 287 Alkaloid Index 289 Taxonomic Index 303 Author Index 315 List of Figures 1 Contemporary scheme of morphine. 2 2 Some alkaloids isolated by pharmaceutists Pierre Joseph Pelletier and Joseph Beinamé Caventou during 1817–1821. 3 3 Schemes of taxol, vinblastine, vincristine and vincamine 5 4 An example of a true alkaloid 11 5 An example of protoalkaloids 11 6 An example of a pseudoalkaloid 12 7 The raw extraction of quinolizidine alkaloids 13 8 l-tryptophan with its aromatic side chain 15 9 The devil’s-pepper genus, Rauwolfia serpentina 15 10 l-phenylalanine is a precursor 17 11 l-ornithine is an important precursor 19 12 l-tyrosine, with its aromatic side chain 19 13 l-anthranilic acid is a precursor 23 14 l-histidine is a precursor 24 15 l-ornithine and l-nicotinic acids are precursors 26 16 l-lysine is a precursor 31 17 (a) Structure of seed testa of the Washington lupine (b) Alkaloidal Lupinus polyphyllus Lindl. 32 18 Jervine, cyclopamine and protoveratrine structures. 49 19 Basic alkaloids of mushrooms. 55 20 Ergotamine and LSD 56 21 Secondary metabolism blocks 65 22 Pyruvate derivation and acetyl CoA synthesis 66 23 General scheme of alkaloid synthesis 68 24 l-lysine-derived nuclei 69 25 Nuclei and skeletons of izidine alkaloids 70 26 The source and forms of the pyrrolidine ring 70 27 l-histidine and the nuclei of imidazole and manzamine alkaloids. 70 28 The nuclei produced by anthranilic acid in alkaloids 71 29 The nucleus of alkaloids derived from nicotinic acid 72 30 l-phenylanine-derived nuclei in alkaloid biosynthesis 72 31 Nuclei supplied to alkaloids by l-tyrosine in the synthesizing process 73 32 The l-tryptophan-supplied nucleus during synthesis 74 33 Synthesis of alkaloids