New Natural Products and Plant Drugs with Pharmacological, Biological or Therapeutical Activity: Proceedings of the First International Congress on Medicinal Plant Research, Section A, held at the University of Munich, Germany, September 6–10, 1976 PDF
Preview New Natural Products and Plant Drugs with Pharmacological, Biological or Therapeutical Activity: Proceedings of the First International Congress on Medicinal Plant Research, Section A, held at the University of Munich, Germany, September 6–10, 1976
Proceedings in Life Sciences First International Congress on Medicinal Plant Research, held at the University of Munich, Germany, September 6-10, 1976. Section B: Plant TIssue Culture and Its Bio-technological Application. Eds.: W.BarzjE.ReinhardjM.H.Zenk. Published by Springer-Verlag Berlin Heidelberg New York 1977. New Natural Products and Plant Drugs with Pharmacological, Biological or Therapeutical Activity Proceedings of the First International Congress on Medicinal Plant Research, Section A, held at the University of Munich, Germany September 6-10, 1976 Edited by H. Wagner and P. Wolff With 152 Figures Springer-Verlag Berlin Heidelberg New York 1977 Prof. Dr. H. WAGNER Dr. P.WOLFF Institut fUr Pharmazeutische Arzneimittellehre UniversiHit MUnchen KarlstraBe 29,8000 MUnchen 2/FRG Cover motive: Left: a shoot of May tenus buchanan ii, a bush or tree growing in Central West Africa, belonging to the Celastraceae. Right: structure of mayt ans in, isolated from the plant. ISBN-13: 978-3-642-66684-1 e-ISBN-13: 978-3-642-66682-7 DOl: 10.1007/978-3-642-66682-7 Library of Congress Cataloging in Publication Data. International Congress on Medicinal Plant Research, 1st, University of Munich, 1976. New natural products and plant drugs with pharmacological, biological or therapeutical activity. (Proceedings in life sciences) Includes bibliographies and index. 1. Materia medica, Vegetable-Congresses. I. Wagner, Hiidebert, 1929-. II. Wolff, Peter Maria, 1932-. III. Title. [DNLM: 1. Drugs-Congresses. 2. Plants, Medicinal-Con gresses. W3 IN632M 1976/QV7661611976n]. RS 164.156.1976.615'.32.77-8846. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to the publisher, the amount of the fee to be determined by agreement with the publisher. © by Springer-Verlag Berlin Heidelberg 1977. Softcover reprint of the hardcover 1st edition 1977 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 2131/3130-543210 Preface The fact that, of the approximately 600,000 plant species existing on the earth, only some 5 % have been specifically investigated chemically or pharmacologi cally, is a challenge to chemists spezializing in na tural substances and to pharmacologists. In view of the limited number of research capacities and the ever diminishing financial means, this challenge can only be met if, together with an improvement and refinement of methods of analysis, medicinal plant research is carried out on a broader interdisciplinary basis, with comparable, scientifically recognized screening methods, and if it is better coordinated, with greater use of modern documentation means. It is thus necessary in the future to concentrate specifically on projects leading to the development of new medicinal prepara tions. The plenary lectures hold in the present symposium of the 1st International Congress for Research on Medi cinal Plants reflect these efforts and tendencies. At the same time they provide a survey of some of the fields of medicinal plant research which are at present most actual and most intensively researched. They range from plant screening, isolation and structure eluci dation of new principles, to the therapeutical opti mization of a natural product. The lectures given at this congress show clearly the necessity, in addition to national phytochemical so cieties, for a central international organisation, in which all active medicinal plant researchers in the world are included. Their aim should be to provide the impulse for more optimal, rational research, aimed at the solution of specific projects. The symposium was generously supported by the Deutsche Forschungsgemeinschaft (Bonn) and various chemical and pharmaceutical industries. June, 1977 H. WAGNER P. WOLFF Contents Problems and Prospects of Discovering New Drugs from Higher Plants by Pharmacological Screening N.R. FARNSWORTH and A.S. BINGEL ••.•.•••••.•..••.. A. Introduction ••••.••••••••••••••...••..•••.•••• B. Value of Drugs Obtained from Higher Plants .••. I. Commercial Value of Plant-Derived Drugs .•.. II. Role of Plant-Derived Drugs as Therapeutic Agents ••••.••.•••••••.•.•••.•••••.•••..•.• 3 III. Uses Other than as Drugs for Plant-Derived Chemical s •.•••••••••..•..••••••.••.•••••• 5 C. Apathy in Plant-Derived Drug Development ...•.• 6 D. Current Level of Worldwide Research on Plant- Deri ved Drugs ••••..•..••...•••••..•••.•....... 10 E. Pharmacological Screening Programs for Plant Extracts ...•..••••....•••.•••••.•.••.•.•••.•.• 14 I. Random Selection Approach ••••..•..•......•• 14 II. Selection of Plants Containing Specific Types of Chemical Compounds ..•.••.•••.•••• 15 III. Selection of Plants Based on a Combination of Criteria ...•.•••••.•••..•.•..••.•..•.. 16 F. Problems in the Pharmacological Screening of Extracts from Higher Plants ......•.•.••.••..•• 17 I. Variation from Sample to Sample ••••••••••.• 17 II. Unexpected Dose-Response Relationships •... 17 III. Variation Within Samples from the Same Lot of Plant Material ••••.•.••••.••...•.. 18 IV. Failure to Obtain Positive Results with an Extract Containing Active Principles ...... 19 V. Miscellaneous Considerations in Screening Plant Extracts ..•.••••...•••••.•..•.•••.•.• 20 G. Prospects for the Future ••.•.•••....•.•••.•••. 21 References ••.•••••.•.••.•......•......•.••••..•.. 22 Pharmacological Approaches to Natural Product Screening and Evaluation M.H. MALONE (With 6 Figures) •..••••••••..•..••.•• 23 A. Ideal Requirements for a Primary Screen .••••.. 23 B. Past Approaches to Primary Pharmacological Screening .•..•.••••.•.•.....•.•••...••.....•.. 24 I. Single Technique-Single Goal Screening .•••. 25 II. Screening Using a Battery of Specific Procedures •••.•..••••.•••••••..••.•••••... 25 III. Single Technique-Multiple Goals Screening 25 IV. Combinations of Specific and Multipurpose Procedures •...•.•.•.•.••.•.•••••••..•..•.. 26 C. Multidimensional Primary Screening .••..••.•.•• 27 I. The Rat "Hippocratic" Screen •..••..••••..•• 27 VIII 1. Variations of Hippocratic Screening .•••. 30 2. Computerized Hippocratic Evaluation •.••• 31 II. The Mouse Multidimensional Screen .•.••.... 35 III. Relative Merits of the Mouse and Rat Primary Screens •••.••.••.•••..••.....•... 35 D. Multidimensional Secondary Screening of Extracts and Pure Compounds •.•••..••.••.••.••. 37 I. The Dog Pharmacodynamic Screen ••..•.•..•.•• 38 II. Other Approaches to Secondary Evaluation •• 39 E. Tertiary Eval ua tion .••••••••.••...•.••.•••.•.. 40 F. Addendum-Sample Print-Out of Computerized Hippocratic Evaluation •••.....••.••..•..••••.• 41 References •••..•...••.•••••.•....•...•••••••..••• 50 Recent Experimental and Clinical Data Concerning Antitumor and Cytotoxic Agents from Plants G.A. CORDELL ••.•••.•••.••.•••••••..••••••..••••.• 54 A. Introduction ••..•••...•••.•••.•.••..•..•••.•.• 54 B. Terpenoids ••.•...•••••...•.•••••.•.•.•••.....• 55 I. Sesquiterpenes ..•.•.•••••••.••..•••.•.••.•• 55 II. Di terpenes •...•••••.••..••.•..•..••.•.•••. 57 III. Simaroubolides •.•••.••.....•.......•..••• 59 C. Miscellaneous Compounds •...•.....••..••..••••• 60 D. Alkaloids •.•.......•••.•.•.....••.•.•••...•••• 61 I. Pyrrolizidine Alkaloids •..••••••••.••.•••.. 62 II. Isoquinoline Alkaloids ...•••...••••.••...• 62 III. Benzophenanthridines ..•....•.•••••..•..•. 63' IV. Miscellaneous Alkaloids ..••.•.•••..•.••••• 65 V. Monomeric Indole Alkaloids .• , ...••..•••...• 66 VI. Camptothec ine .•.•••••••..•.••..•••.•....•• 67 VII. CephaZotaxus Alkaloids . . • . . • . . • • • • • • • • • • .. 68 VIII. Dimeric Indole Alkaloids ..••.•......••.• 70 IX. Maytansinoids .•.••••.••...•....••.•••..••. 74 E. Summary ..........••..•••••••.••.•.•..•...••••. 75 References •.•..••.•••..••••••.•.••.•.••••.•.•.••• 75 Recent Advances in the Field of Antibiotics CH. TAMM (With 25 Figures) .••••.••....••.••••...• 82 A. Introduction .•••.•••••••••••.••••....••••••... 82 B. Acetate/Propionate-Derived Metabolites .••..••. 83 I. Tetracyc 1 ines •....•••••.••••...•••.••.•.... 83 II. Anthracyclines •.••••..••.••.•.•••..•••...• 85 III. Aflatoxins .•••.•...•••.•.•••.••.••.••...• 86 IV. Macrolides •.••••.•.•••••••••...••.•.•.•••. 87 V. Cytochalasans .••............••.••••••••.••• 88 VI. Polyethers ..••.•.•....•.•.••..••..•••.•... 91 VII. Macrotetrolides .•.••••••.•.....•....•.•.• 92 VIII. Nonadrides •...•••...•..••.•.•.•......••. 93 IX. Ansamycins •••.•.....•••••..•.•...•.•..•••. 94 X. Ovalicin and Pseurotins •...••..•...•.•.•... 95 C. Isoprenoid Metabolites ••..•...•••.•••..•••.... 96 D. Amino Acid-Derived Metabolites ..•.•••••.••••.. 100 I. Penicillins and Cephalosporins ••.•...•.•••. 100 II. Other Natural B-Lactams ..•••..•..•.•.••••. 102 III. Cyclic Polypeptides ••..•••.•.•.••.•••..•• 102 E. Conclusion •.•...••.•..••.••.•.•.•.•...••..•••. 104 References .••..•••...•..•.•..••..•...•.......•.•• 104 IX Progress in the Chemistry of Alkaloids with Pharma cological or Biological Activity H. ACHENBACH (With 7 Figures) .••••••••••••..•.•.. 108 References ••.•••••....••.•.••••..........•••...•• 132 Plant Mono-,Di- and Sesquiterpenoids with Pharma cological or Therapeutical Activity o. STICHER (With 23 Figures) ..••.•.....•••..••... 137 A. Introduction .•.••.••.•.....•.•••.•••.••.•..... 137 B. Classif ication •••....•••.••.•••.........•.•... 137 C. General Biological Properties ••••..•••••..•••. 137 D. Monoterpenes .•••.•••.••.••.•••••••••••...•••.• 1 40 I. Normal Monoterpenes •.•.••••••••.••.•..•••.. 140 1. Antiseptic, Disinfectant, Anthelmintic Properties ••.••.••••••••••••..••.•.••.•• 1 42 2. Irritant, Skin Stimulant, Expectorant, Diuretic Properties ..•.•.......•..•.•..• 143 3. Sedative, Carminative, Spasmolytic Properties ...••••..•.•••••••.•••.•.....• 144 II. Cyclopentanoid Monoterpenes and Derivatives •.•..•.•.••••..•.•.•.....•••.•. 145 1. Biological Activity of the Methyl cyclopentanoid Monoterpenes of the Nepetalactone Type ••••••••••••••.•.•.••. 148 2. Pharmacological Activity of the Iridoids and Secoiridoids •••••.••..••••.•..•.••.. 148 Antimicrobial Activity •••••••••••.••••.• 148 Hypotensive Effect •••••.•.•.••.••.•..••• 150 Analgetic and Antiphlogistic Properties 150 Bi tter Tonic ••......•••••••••.•.••••.••• 152 Sedative Agents ••••.....••..••••.••..•.• 153 Laxative Properties •.•.•....••••..•..•.• 153 Antileukemic Activity .•...•..•..•.•..••• 155 Various Other Effects ••••••••.•••....... 155 3. Cantharidin .••••.••..••••••.••••....•..• 156 ~. Sesquiterpenes and Diterpenes ..•.•.•••.......• 157 I. Antiphlogistic and Spasmolytic Agents ..•••• 157 II. Bitter Substances .••••.•••••••.••.•.•.•••• 159 III. Antitumor Activity •..•••••.•.•.•••••••.•• 160 F. Conclusion •••••••••.•••••.••••••••••••••••.•.. 165 References .•••.•.••.•.••••••....•.•.•••••........ 166 Saponins with Biological and Pharmacological Activity S. SHIBATA (With 9 Figures) .•••.•.••....•.•...•.. 177 A. Introduction •..••.•.•.•..•.•...•••••.•........ 177 B. Saponins of Licorice .•.•..••••••...•...•...... 178 I. Corticoidal Activities of Glycyrrhizin •.••. 178 II. Antiinflammatory Activities of Glycyrrhizin 179 III. Antigastric Ulcer Effects of Glycyrrhizin 180 IV. Metabolic Effects of Glycyrrhizin ••••.•..• 180 C. The Saponins of Bupleuri Radix and Platycodi Radix ••••••••••..••••.••..••.•••..•.•..•••.... 180 D. Saponins of Polygalae Radix and Senegae Radix .•. 183 E. Saponins of Akebiae Vitis ••••••••••••••••••••••• 184 x F. Aescin, the Saponins of the Seeds of Aesculus hippoc as tanwn •••••••.•••.•••••••.•••••.•••..•••• 1 84 G. Saponins of Ginseng •••••••••.•••••••...•••..•• 185 I. Chemical Studies on the Saponins and Sapo genins of Ginseng and its Congeners .••.•••• 185 II. Pharmacological and Biochemical Studies on Ginseng Saponins •.•.•••..••..••.....•.••.• 1 87 III. Pharmacological Studies on Japanese Chikusetsu-Ginseng •••..••.••••..•.••••••• 190 H. Saponins of Zizyphus Spinosi Semen •••..•••••.•.•• 1 91 I. Concluding Remarks .•.•.••..•...•••.••••..•••.• 192 References •.•••.•.•.•.••.•.•••..•.••.•.•...•..•.• 192 Dimeric Natural Compounds with Pharmacological Activity A.E. SCHWARTING ••••••...•..•••.•.•.•••••..••...•• 197 A. Definitions and Classification •.•••.•.•..•••.• 197 B. The Formation of Dimeric Compounds •••.••...•.• 203 C. Pharmacological and Physiological Activity •••• 205 I. Lignahs .•..•••..•••..•••••.••••.••.•..••.•• 206 II. Dimeric Photosensitizers •......•••••.....• 209 III. Coumarins •••••.•..•.•••.......•...••.•.•• 209 References ••••.•...•••.••••.•...•.•.•••••••••..•. 210 Chemical and Biological Investigations on Indian Medicinal Plants T.R. GOVINDACHARI (With 21 Figures) •..•..•..••.•. 212 A. Introduction •.•...••••.•...•......•.......•..• 212 B. Alkaloids •....••.••.•••.•••....•.•..•..•.•.... 212 I. Tylophora Alkaloids •.••.......•.•.••.••••.• 212 II. Ancistrocladus Alkaloids •••••.•••••••••... 213 III. Alkaloids of Croton sparsifiorus Morong •...• 214 IV. Alkaloids of Mappia foetida Miers ••..•.•••.. 214 V. Alkaloids of Piper trichostachyon C. Dc. .•..... 214 VI. Alkaloids from some Menispermaceae Plants 215 1. Alkaloids from TiZiacora racemosa Colebr. • •. 215 2. Alkaloids of CoccuZus penduZus (Forsk) Diels and CoccuZus ZaurifoZius Dc. '" . . . . . • . • . . . .. 216 3. Alkaloids of CissampeZos pareira Linn. .••.• 216 C. Oxygen Heterocycles ..•••••••..•...••.•.••••••. 216 I. Cryptocaryalactone and Cryptocaryone ••....• 216 II. Surangin A and B .••...•.•.••..•.••.•.•..•. 217 III. Tuberosin ...••....•.•..•.....••....•..... 217 D. Terpenoids ..•..••••••..•.••...•.•••....•.•.•.. 217 I. Sesqui terpenes of Cedrus deodara Loudon •.•..• 217 II. Enhydrin ...••.•.••••......•...•..•..•...•• 218 III. Tagitinins A and F ••.....•.•....••..•••.. 218 IV. Coleonol •.....•••.....••.••......••...•..• 218 V. Diosbulbine .•...••••..•..••.....••..••.••.• 218 VI. Dysobinin ......••...••.•......•....•..•.•. 218 VII. Triterpenes of SaZacia prinoides DC .•••.•.. 219 E. Glycosides .••....•••.••••....•••....••....•..• 219 I. Cleistanthin ..•....•.•.....•..•..••••.••... 21 9 II. Ipolearoside •.•.•..••...........•.••..•..• 220 III. Stigmasta-7, 22-diene-3S-0-glucoside 220 IV. Scuttelarein-5-glucuronide ..••.••.•••....• 220 XI V. Glycosides of Picrorhiza kurrooa Benth. •.. . . . .• 220 VI. Asclepin ••.•..••••.••••••••.••.••..•••...• 220 VII. Shatavarins I - IV •.•...••.••...••.•..•.• 221 VIII. Glycosides of Carissa Species .••......... 221 IX. Peruvoside ...•....•.•••..••.....•........• 221 F. Miscellaneous •....•..•..••......•....••......• 222 I. Curcurnine •.•.•....•..•••.••••..••....••.... 222 II. Arnebin •....•..••.....••••.....•......••.. 222 III. Diospyrol •.•••••..•.••..•••.••••...•...•• 222 IV. Steroidal Constituents of Commiphora mukuZ ..• 222 References ..•••.••..••..••••••.•...•..•.••..•..•• 224 Chemistry of Neolignans with Potential Biological Activity O.R. GOTTLIEB (With 20 Figures) ••••..••....•..•.. 227 A. Introduction .•.•••.•••.••.••.••.•...•.•.•.•.•. 227 B. Benzofuranoid Neolignans ••••••..•••••...•••••• 229 I. Di- and Tetrahydrobenzofurans .•••.••••••.•. 229 II. Hexahydrobenzofurans •••••.••..•...•.•••••. 233 C. Benzodioxane and Other Neolignans •...•..•....• 236 D. Bicyclo [3,2,1] octanoid Neolignans •..•••.•... 239 E. Biogenesis of Neolignans •...•••......••••••••• 242 F. Conclusion .•.•..••••...•..........•.....•..•.. 244 References ..•....••.••.•••.••.••.•.••••.•.•.••..• 246 Natural Substances with Effects on the Liver G. VOGEL (With 20 Figures) ...••..•.•.•.••..•••••. 249 References ......•..•........•..•.......••..••...• 262 The Modification of Natural Substances in the Modern Drug Synthesis P.W. THIES (With 21 Figures) .••.•...•.......••..• 266 A. Introduction ....•.•.•.•..•......•......•...... 266 B. Main Part ..•....•.•••.••....•...•.......••..•• 267 I. Steroids and Prostanoids •.....•..•••••..... 267 II. "Chemotherapy" ...•..•....•.....•....•.•..• 268 III. Claviceps Purpurea •.•...••••.•.•.•.•••.•. 270 1. Peptide Alkaloids (13-15) .....•...•..•. 272 (a) Ergotamine (2) •..••...•••.....••••... 272 (b) Dihydroergotamine •......•.•.•..••.•. 272 (c) Dihydroergotoxines ..•••..••..•.•..•. 272 (d) 2-Bromo-a-ergocryptine = CB 154 (16). 273 2. Low-Molecular Lysergic Acid Derivatives 273 Lysergic Acid Diethylamide ..•.••.••.•... 273 Methylergobasine .••.••...••••.•••......• 273 Methysergide ..............•.•.....••••.. 273 IV. Opiates .•••••...•...•.....••..•.•......... 274 V. Cannabinoids .•.......•...•......•.....••.•• 276 VI. Natural Substances in the Role of Raw Material for Drug Synthesis and Biochemical Model Reactions .....•.••......••.•.•...... 277 References •.•...•....•••...•......•.............. 282 Subj ect Index ..•..•...............•....•......... 284
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