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medicinal natural products paul m dewick copyright 2002 john wiley sons ltd isbns 0471496405 hardback 0471496413 paperback 0470846275 electronic medicinal natural products a biosynthetic approach second edition

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medicinal natural products a biosynthetic approach second edition school of pharmaceutical sciences university of nottingham uk paul m dewick

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copyright 2002 by john wiley sons ltd baffins lane chichester west sussex po19 1ud england national 01243 779777 international 44 1243 779777 e-mail for orders and customer service enquiries cs-books@wiley.co.uk visit our home page on http www.wiley.co.uk or http www.wiley.com 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 scanning or otherwise except under the terms of the copyright designs and patents act 1988 or under the terms of a licence issued by the copyright licensing agency 90 tottenham court road london w1p 9he uk without the permission in writing of the publisher with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system for exclusive use by the purchaser of the publication neither the authors nor john wiley sons ltd accept any responsibility or liability for loss or damage occasioned to any person or property through using the material instructions methods or ideas contained herein or acting or refraining from acting as a result of such use the authors and publisher expressly disclaim all implied warranties including merchantability of fitness for any particular purpose designations used by companies to distinguish their products are often claimed as trademarks in all instances where john wiley sons is aware of a claim the product names appear in initial capital or capital letters readers however should contact the appropriate companies for more complete information regarding trademarks and registration other wiley editorial offices john wiley sons inc 605 third avenue new york ny 10158-0012 usa wiley-vch verlag gmbh pappelallee 3 d-69469 weinheim germany john wiley australia ltd 33 park road milton queensland 4064 australia john wiley sons canada ltd 22 worcester road rexdale ontario m9w 1l1 canada john wiley sons asia pte ltd 2 clementi loop #02-01 jin xing distripark singapore 129809 library of congress cataloguing in publication data dewick paul m medicinal natural products a biosynthetic approach paul m dewick ­ 2nd ed p cm includes bibliographical references and index isbn 0 471 49640 5 cased ­ isbn 0 471 49641 3 pbk 1 natural products 2 biosynthesis 3 pharmacognosy i title rs160 .d48 2001 615 .321 ­ dc21 2001026766 british library cataloguing in publication data a catalogue record for this book is available from the british library isbn 0 471 49640 5 cased isbn 0 471 49641 3 pbk typeset by laserwords private ltd chennai india printed and bound in great britain by antony rowe ltd chippenham wilts this book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production.

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dedicated to the many hundreds of pharmacy students i have taught over the years who unknowingly have encouraged me to write this text

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contents 1 about this book and how to use it the subject the aim the approach the topics be selective to learn or to understand conventions regarding acids bases and ions nomenclature some common abbreviations further reading 2 secondary metabolism the building blocks and construction mechanisms primary and secondary metabolism the building blocks the construction mechanisms alkylation reactions nucleophilic substitution alkylation reactions electrophilic addition wagner­meerwein rearrangements aldol and claisen reactions schiff base formation and the mannich reaction transamination decarboxylation reactions oxidation and reduction reactions dehydrogenases oxidases mono-oxygenases dioxygenases amine oxidases baeyer­villiger oxidations phenolic oxidative coupling glycosylation reactions some vitamins associated with the construction mechanisms vitamin b1 vitamin b2 vitamin b5 vitamin b6 vitamin b12 vitamin h further reading 3 the acetate pathway fatty acids and polyketides saturated fatty acids unsaturated fatty acids fixed oils and fats evening primrose oil acetylenic fatty acids branched-chain fatty acids echinacea 1 1 1 2 2 2 3 3 3 4 4 7 7 8 12 12 13 15 15 18 20 20 24 24 25 25 27 28 28 28 29 30 33 35 36 40 47 48

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viii contents prostaglandins prostaglandins isoprostanes thromboxanes thromboxanes leukotrienes leukotrienes aromatic polyketides cyclization simple phenols structural modifications anthraquinones senna cascara frangula allied drugs hypericum/st john s wort c-alkylation reactions mycophenolic acid khellin and cromoglicate phenolic oxidative coupling griseofulvin oxidative cleavage of aromatic rings starter groups other than acetate poison ivy and poison oak aflatoxins cannabis tetracyclines anthracycline antibiotics macrolides and polyethers extender groups other than malonate macrolide antibiotics avermectins polyene antifungals tacrolimus and sirolimus ansa macrolides cyclization through diels­alder reactions mevastatin and other statins genetic manipulation of the acetate pathway further reading 4 the shikimate pathway aromatic amino acids and phenylpropanoids aromatic amino acids and simple benzoic acids folic acid vitamin b9 chloramphenicol cinnamic acids lignans and lignin podophyllum phenylpropenes volatile oils containing principally aromatic compounds benzoic acids from c6 c3 compounds coumarins dicoumarol and warfarin psoralens styrylpyrones kava flavonoids and stilbenes flavonolignans silybum marianum isoflavonoids phyto-oestrogens derris and lonchocarpus terpenoid quinones vitamin e vitamin k further reading 51 58 58 60 61 63 72 76 78 79 92 92 111 114 117 121 121 130 132 135 141 142 147 149 151 154 158 164

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contents ix 5 the mevalonate and deoxyxylulose phosphate pathways terpenoids and steroids hemiterpenes c5 monoterpenes c10 volatile oils containing principally terpenoid compounds irregular monoterpenes pyrethrins iridoids c10 valerian sesquiterpenes c15 feverfew chamomile and matricaria artemisia annua and artemisinin gossypol trichothecenes diterpenes c20 taxus brevifolia and taxol paclitaxel ginkgo biloba forskolin sesterterpenes c25 triterpenes c30 triterpenoid saponins liquorice quillaia ginseng modified triterpenoids tetraterpenes c40 vitamin a higher terpenoids steroids stereochemistry cholesterol cholesterol steroidal saponins dioscorea fenugreek sisal sarsaparilla yucca cardioactive glycosides digitalis purpurea digitalis lanata strophanthus convallaria squill toxic plants phytosterols soya bean sterols fusidic acid vitamin d vitamin d bile acids bile acids adrenocortical hormones/corticosteroids semi-synthesis of corticosteroids corticosteroid drugs progestogens progestogen drugs oestrogens oestrogen drugs aromatase inhibitors oestrogen receptor antagonists androgens androgen drugs further reading 167 172 172 186 187 191 203 212 212 219 225 226 231 232 232 233 237 241 252 257 260 262 264 267 282 285

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x contents 6 alkaloids alkaloids derived from ornithine pyrrolidine and tropane alkaloids belladonna stramonium hyosycamus duboisia allied drugs hyoscyamine hyoscine and atropine coca pyrrolizidine alkaloids alkaloids derived from lysine piperidine alkaloids lobelia quinolizidine alkaloids indolizidine alkaloids alkaloids derived from nicotinic acid pyridine alkaloids vitamin b3 tobacco areca alkaloids derived from tyrosine phenylethylamines and simple tetrahydroisoquinoline alkaloids catecholamines areca lophophora curare modified benzyltetrahydroisoquinoline alkaloids opium phenethylisoquinoline alkaloids colchicum terpenoid tetrahydroisoquinoline alkaloids ipecacuanha amaryllidaceae alkaloids galanthamine alkaloids derived from tryptophan simple indole alkaloids 5-hydroxytryptamine serotonin psilocybe simple -carboline alkaloids terpenoid indole alkaloids rauwolfia catharanthus iboga nux-vomica ellipticine quinoline alkaloids cinchona camptothecin pyrroloindole alkaloids physostigma ergot alkaloids ergot morning glories alkaloids derived from anthranilic acid quinazoline alkaloids quinoline and acridine alkaloids alkaloids derived from histidine imidazole alkaloids pilocarpus alkaloids derived by amination reactions acetate-derived alkaloids conium maculatum phenylalanine-derived alkaloids ephedra khat terpenoid alkaloids aconite 291 292 292 305 307 307 308 309 310 311 311 315 315 327 329 341 343 345 346 347 349 350 359 365 368 376 377 377 379 379 381 381 382 385

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contents xi steroidal alkaloids solanum alkaloids purine alkaloids caffeine theobromine and theophylline coffee tea cola cocoa mat´ tea e guarana saxitoxin and tetrodotoxin saxitoxin tetrodotoxin further reading 7 peptides proteins and other amino acid derivatives peptides and proteins ribosomal peptide biosynthesis peptide hormones thyroid hormones thyroxine calcitonin hypothalamic hormones thyrotrophin-releasing hormone luteinizing hormone-releasing hormone growth hormone-releasing hormone/factor somatostatin anterior pituitary hormones corticotropin growth hormone prolactin gonadotrophins posterior pituitary hormones oxytocin vasopressin pancreatic hormones insulin glucagon interferons interferons opioid peptides enzymes nonribosomal peptide biosynthesis peptide antibiotics cycloserine polymyxins bacitracins tyrothricin and gramicidins capreomycin vancomycin and teicoplanin bleomycin cyclosporins streptogramins dactinomycin peptide toxins death cap amanita phalloides ricin botulinum toxin microcystins snake venoms modified peptides penicillins cephalosporins and other -lactams penicillins penicillins cephalosporins cephalosporins cephamycins carbacephems other -lactams clavulanic acid carbapenems monobactams cyanogenic glycosides glucosinolates cysteine sulphoxides garlic further reading 388 394 396 398 405 405 407 410 410 411 413 413 416 417 417 419 421 423 433 422 422 444 450 455 457 460 461

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xii contents 8 carbohydrates monosaccharides oligosaccharides monosaccharides and disaccharides vitamin c polysaccharides polysaccharides aminosugars aminoglycosides aminoglycoside antibiotics streptamine-containing antibiotics 2-deoxystreptamine-containing antibiotics acarbose lincomycin and clindamycin further reading index 465 465 469 473 477 478 486 487

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medicinal natural products paul m dewick copyright 2002 john wiley sons ltd isbns 0471496405 hardback 0471496413 paperback 0470846275 electronic 1 about this book and how to use it an introductory chapter briefly describing the subject the aim the approach and the topics students are offered advice on how to select material for study and encouraged to understand the information rather than learn the factual material general information on ionization in biochemicals and on nomenclature is given together with a list of common abbreviations the subject this book has been written primarily for pharmacy undergraduates to provide a modern text to complement lecture courses dealing with pharmacognosy and the use of natural products in medicine nevertheless it should be of value in most other courses where the study of natural products is included although the examples chosen are predominantly those possessing pharmacological activity for centuries drugs were entirely of natural origin and composed of herbs animal products and inorganic materials early remedies may have combined these ingredients with witchcraft mysticism astrology or religion but it is certain that those treatments that were effective were subsequently recorded and documented leading to the early herbals the science of pharmacognosy ­ the knowledge of drugs ­ grew from these records to provide a disciplined scientific description of natural materials used in medicine herbs formed the bulk of these remedies as chemical techniques improved the active constituents were isolated from plants were structurally characterized and in due course many were synthesized in the laboratory sometimes more active better tolerated drugs were produced by chemical modifications semi-synthesis or by total synthesis of analogues of the active principles gradually synthetic compounds superseded many of the old plant drugs though certain plant derived agents were never surpassed and remain as valued medicines to this day natural drugs derived from microorganisms have a much shorter history and their major impact on medicine goes back only about 60 years to the introduction of the antibiotic penicillin microbially produced antibiotics now account for a very high proportion of the drugs commonly prescribed there is currently a renewed interest in pharmacologically active natural products be they from plants microorganisms or animals in the continued search for new drugs particularly for disease states where our present range of drugs is less effective than we would wish herbal remedies are also enjoying a revival as many sufferers turn away from modern drugs and embrace `complementary medicine the aim many modern university pharmacy courses include a pharmacognosy component covering a study of plant-derived drugs and traditionally this area of natural products has been taught separately from the microbially derived antibiotics or the animalrelated steroidal and prostanoid drugs these topics usually form part of a pharmaceutical chemistry course the traditional boundaries may still remain despite a general change in pharmacognosy teaching from a descriptive study to a phytochemical-based approach a trend towards integrating pharmacognosy within pharmaceutical

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2 about this book and how to use it chemistry and the general adoption of modular course structures a chemistry-based teaching programme encompassing all types of natural product of medicinal importance semi-synthetic derivatives and synthetic analogues based on natural product templates is a logical development and one we have practised at nottingham for several years this coursebook provides a suitable text for such a programme and attempts to break down the artificial divisions the approach this book establishes a groundwork in natural product chemistry/phytochemistry by considering biosynthesis ­ the metabolic sequences leading to various selected classes of natural products this allows application of fundamental chemical principles and shows the relationships between the diverse structures encountered in nature thus giving a rationale for natural products and replacing the traditional descriptive approach with one based more on deductive reasoning subdivision of the topics is predominantly via biosynthesis not class or activity and this provides a logical sequence of structural types and avoids a catalogue effect there is extensive use of chemical schemes and mechanism with detailed mechanistic explanations being annotated to the schemes as well as outline discussions in the text extensive cross-referencing is used to emphasize links and similarities as important classes of compounds or drugs indicated by an asterisk are reached more detailed information is then provided in the form of short separate monographs in boxes which can be studied or omitted as required in the latter case allowing the main theme to continue the monograph information covers sources production methods principal components drug use mode of action semi-synthetic derivatives synthetic analogues etc as appropriate those materials currently employed as drugs are emphasized in the monographs by the use of bold type should be familiar having been met previously in courses dealing with the fundamentals of organic chemistry and biochemistry these principles are then seen in action as representative natural product structures are described in the following chapters these are subdivided initially into areas of metabolism fed by the acetate shikimate mevalonate and deoxyxylulose phosphate pathways remaining chapters then cover alkaloids peptides and proteins and carbohydrates the book tries to include a high proportion of those natural products currently used in medicine the major drugs that are derived from natural materials by semi-synthesis and those drugs which are structural analogues some of the compounds mentioned may have a significant biological activity which is of interest but not medicinally useful the book is also designed to be forward looking and gives information on possible leads to new drugs a selection of supplementary reading references is provided at the end of each chapter these are limited as far as possible to recent review articles in easily accessible journals rather than books and have been chosen as student friendly be selective coverage is extensive to allow maximum flexibility for courses in different institutions but not all the material will be required for any one course however because of the many subdivisions and the highlighted keywords it should be relatively easy to find and select the material appropriate to a particular course on the other hand the detail given in monographs is purposely limited to ensure students are provided with enough factual information but are not faced with the need to assess whether or not the material is relevant even so these monographs will undoubtedly contain data which exceed the scope of any individual course it is thus necessary to apply selectivity and portions of the book will be surplus to immediate requirements the book is designed to be user friendly suitable for modular courses and student-centred learning exercises and a starting point for later project and dissertation work the information presented is as up to date as possible but undoubtedly new research will be published that modifies or even contradicts some of the statements made the reader is asked always to be critical and to maintain the topics a preliminary chapter is used to outline the main building blocks and the basic construction mechanisms employed in the biosynthesis of natural products many of these fundamental principles

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about this book and how to use it 3 a degree of flexibility when reading the scientific literature and to appreciate that science is always changing acids are shown in unionized form although they will typically exist as zwitterions r co2h r co2 to learn or to understand the primary aim of the book is not to rely just on factual information but to impart an understanding of natural product structures and the way they are put together by living organisms rationalization based on mechanistic reasoning is paramount the sequences themselves are not important the mechanistic explanations for the processes used are the essence students should concentrate on understanding the broad features of the sequences and absorb sufficient information to be able to predict how and why intermediates might be elaborated and transformed the mechanistic explanations appended to the schemes should reinforce this approach anyone who commits to memory a sequence of reactions for examination purposes has missed the point of course passing exams is probably the main reason why students are prompted to read this book and the retention of some factual information will be essential there is no alternative to memory for some of the material covered in the monographs but wherever possible information should be reduced to a concept that can be deduced rather than remembered the approach used here should help students to develop such deductive skills h nh2 h nh3 ionized and unionized forms of many compounds are regarded as synonymous in the text thus acetate/acetic acid shikimate/shikimic acid and mevalonate/mevalonic acid may be used according to the author s whim and context and have no especial relevance nomenclature natural product structures are usually quite complex some exceedingly so and fully systematic nomenclature becomes impracticable names are thus typically based on so-called trivial nomenclature in which the discoverer of the natural product exerts his or her right to name the compound the organism in which the compound is found is frequently chosen to supply the root name e.g podophyllotoxin and peltatins from podophyllum peltatum name suffixes might be -in to indicate `a constituent of -oside to show the compound is a sugar derivative -genin for the aglycone released by hydrolysis of the sugar derivative -toxin for a poisonous constituent or may reflect chemical functionality such as -one or -ol traditionally -ine is always used for alkaloids amines structurally related compounds are then named as derivatives of the original using standard prefixes such as hydroxy methoxy methyl dihydro homo etc for added substituents or deoxy demethyl demethoxy dehydro nor etc for removed substituents positioning being indicated from systematic numbering of the carbon chains or rings some groups of compounds such as steroids fatty acids and prostaglandins are named semisystematically from an accepted root name in this book almost all structures depicted in the figures carry a name this is primarily to help identification and for the student structural features are more pertinent than the names used it will soon become apparent that drug names chosen by pharmaceutical manufacturers are quite random and have no particular relationship to the chemical structure conventions regarding acids bases and ions in many structures the abbreviation p is used to represent the phosphate group and pp the diphosphate or pyrophosphate group opoop phosphate oopopooo pp diphosphate at physiological phs these groups will be ionized as shown but in schemes where structures are given in full the unionized acids are usually depicted this is done primarily to simplify structures to eliminate the need for counter-ions and to avoid mechanistic confusion likewise amino

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4 about this book and how to use it we are also currently experiencing a transitional period during which many established drug names are being changed to recommended international non-proprietary names rinn both names are included here the rinn preceding the older name nad nadh nadp nadph o p p pep pg plp pp pp some common abbreviations acp adp api ara atp b coa cdp ctp dig dmapp enz fad fadh2 fmn fmnh2 fpp fru gal gfpp acyl carrier protein adenosine diphosphate apiose arabinose adenosine triphosphate general base coenzyme a as part of a thioester e.g acetyl-coa ch3 coscoa cytidine diphosphate cytidine triphosphate digitoxose dimethylallyl diphosphate dimethylallyl pyrophosphate enzyme flavin adenine dinucleotide flavin adenine dinucleotide reduced flavin mononucleotide flavin mononucleotide reduced farnesyl diphosphate farnesyl pyrophosphate fructose galactose geranylfarnesyl diphosphate geranylfarnesyl pyrophosphate geranylgeranyl diphosphate geranylgeranyl pyrophosphate glucose geranyl diphosphate geranyl pyrophosphate general acid -hydroxy methylglutaryl coenzyme a coenzyme a isopentenyl diphosphate isopentenyl pyrophosphate leukotriene mannose rha rib sam tdpglc tpp tx udp udpglc utp w­m xyl h nicotinamide adenine dinucleotide nicotinamide adenine dinucleotide reduced nicotinamide adenine dinucleotide phosphate nicotinamide adenine dinucleotide phosphate reduced oxidation ­ in schemes phosphate ­ in text phosphate ­ in structures phosphoenolpyruvate prostaglandin pyridoxal 5 -phosphate diphosphate pyrophosphate ­ in text diphosphate pyrophosphate ­ in structures rhamnose ribose s-adenosyl methionine thymidine diphosphoglucose thiamine diphosphate thiamine pyrophosphate thromboxane uridine diphosphate uridine diphosphoglucose uridine triphosphate wagner­meerwein rearrangement xylose electromagnetic radiation usually uv or visible heat ggpp glc gpp ha hmg-coa hscoa ipp lt mann further reading pharmacognosy phytochemistry natural drugs books bruneton j 1999 pharmacognosy lavoisier andover evans wc 1996 trease and evans pharmacognosy saunders london newall ca anderson la and phillipson jd 1996 herbal medicines a guide for health-care professionals pharmaceutical london.

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