Medicinal Natural Products A Biosynthetic Approach 3rd Ed

546 Pages·2009·6.96 MB·English

Medicinal Natural Products
Medicinal Natural Products: A Biosynthetic Approach, 3rd Edition. Paul M. Dewick
©© 2009 John Wiley & Sons, Ltd. ISBN: 978-0-470-74168-9
Medicinal Natural Products
A Biosynthetic Approach
3rd Edition
Paul M Dewick
formerly University of Nottingham, UK
A John Wiley and Sons, Ltd., Publication
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CONTENTS
1 About thisbook,andhowtouse it . . . . . . . . . . . . . . . . . . . . . . . . . . 1
The subject . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
The aim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
The approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
The topics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
The figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
What tostudy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
What tolearn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Conventionsregardingacids,bases, and ions . . . . . . . . . . . . . . . . . . . . . . . . . 4
Some commonabbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2 Secondary metabolism:thebuildingblocksandconstructionmechanisms . . . . . . . . . . 7
Primary andsecondary metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The buildingblocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
The constructionmechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Alkylationreactions:nucleophilicsubstitution . . . . . . . . . . . . . . . . . . . . . 12
Alkylationreactions:electrophilicaddition . . . . . . . . . . . . . . . . . . . . . . 12
Wagner–Meerweinrearrangements . . . . . . . . . . . . . . . . . . . . . . . . . 15
Aldoland Claisenreactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ImineformationandtheMannichreaction . . . . . . . . . . . . . . . . . . . . . . 18
Aminoacidsandtransamination . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Decarboxylationreactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Oxidationandreductionreactions . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Dehydrogenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Oxidases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Monooxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Dioxygenases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Amineoxidases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Baeyer–Villigermonooxygenases . . . . . . . . . . . . . . . . . . . . . . . 27
Phenolicoxidativecoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Halogenationreactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Glycosylationreactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Elucidatingbiosyntheticpathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
viii Contents
3 Theacetatepathway:fattyacidsandpolyketides . . . . . . . . . . . . . . . . . . . . 39
Fattyacid synthase:saturatedfattyacids . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Unsaturatedfattyacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Uncommon fattyacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Thromboxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Leukotrienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Polyketidesynthases:generalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Polyketidesynthases:macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Polyketidesynthases:linearpolyketidesand polyethers . . . . . . . . . . . . . . . . . . . . 90
Diels–Aldercyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Polyketidesynthases:aromatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Post-polyketidesynthasemodifications . . . . . . . . . . . . . . . . . . . . . . . . 103
Startergroups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
4 Theshikimatepathway:aromaticaminoacidsandphenylpropanoids . . . . . . . . . . . . 137
Aromaticamino acidsandsimplebenzoicacids . . . . . . . . . . . . . . . . . . . . . . . 137
Phenylpropanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Cinnamicacidsandesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Lignansand lignin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Phenylpropenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
BenzoicacidsfromC C compounds . . . . . . . . . . . . . . . . . . . . . . . . 157
6 3
Coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Aromaticpolyketides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Styrylpyrones,diarylheptanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Flavonoidsandstilbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Isoflavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Terpenoidquinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
5 Themevalonateandmethylerythritolphosphatepathways:terpenoids andsteroids . . . . . . 187
Mevalonicacid andmethylerythritolphosphate . . . . . . . . . . . . . . . . . . . . . . . 188
Hemiterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
5
Monoterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
10
Irregularmonoterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Iridoids(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
10
Sesquiterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
15
Diterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
20
Sesterterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
25
Triterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
30
Triterpenoidsaponins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Stereochemistryandnomenclature . . . . . . . . . . . . . . . . . . . . . . . . . 247
Cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
VitaminD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Steroidalsaponins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Cardioactiveglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Bileacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Contents ix
Adrenocorticalhormones/corticosteroids . . . . . . . . . . . . . . . . . . . . . . . 277
Semi-synthesisofcorticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Progestogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Oestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
Androgens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Tetraterpenes(C ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
40
Higherterpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
6 Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Alkaloidsderivedfromornithine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Polyamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Pyrrolidineand tropanealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Pyrrolizidinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Alkaloidsderivedfromlysine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Piperidinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Quinolizidinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Indolizidinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
Alkaloidsderivedfromnicotinicacid . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Pyridinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Alkaloidsderivedfromtyrosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Phenylethylaminesand simpletetrahydroisoquinolinealkaloids . . . . . . . . . . . . . . 336
Modifiedbenzyltetrahydroisoquinolinealkaloids . . . . . . . . . . . . . . . . . . . . 346
Phenethylisoquinolinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Terpenoidtetrahydroisoquinolinealkaloids . . . . . . . . . . . . . . . . . . . . . . 363
Amaryllidaceaealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Alkaloidsderivedfromtryptophan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Simpleindolealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Simpleβ-carbolinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Terpenoidindolealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Quinolinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Pyrroloindolealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Ergotalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Alkaloidsderivedfromanthranilicacid . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Quinazolinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Quinolineandacridinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Alkaloidsderivedfromhistidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Imidazolealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Alkaloidsderivedby aminationreactions . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Acetate-derivedalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Phenylalanine-derivedalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Terpenoidalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Steroidalalkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Purinealkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Saxitoxinandtetrodotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
7 Peptides, proteins, andotheramino acidderivatives . . . . . . . . . . . . . . . . . . . 421
Peptidesandproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Ribosomalpeptidebiosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Peptidehormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
x Contents
Thyroidhormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
Hypothalamichormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Anteriorpituitaryhormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Posteriorpituitaryhormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Pancreatichormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Interferons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Opioidpeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Ribosomalpeptidetoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Non-ribosomalpeptidebiosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Modifiedpeptides:penicillins,cephalosporins,andother β-lactams . . . . . . . . . . . . . . . . 458
Penicillins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Cephalosporins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Otherβ-lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Cyanogenicglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Glucosinolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Cysteinesulfoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
8 Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Monosaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Oligosaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Aminosugarsandaminoglycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Furtherreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
1
ABOUT THIS BOOK, AND HOW TO
USE IT
THE SUBJECT antibioticsnowaccountforaveryhighproportionofthe
drugscommonlyprescribed.Thereiscurrentlyarenewed
This book has been written primarily for pharmacy stu-
interest in pharmacologically active natural products, be
dents to provide a modern text to complement lecture
they from plants, microorganisms, or animals, terrestrial
courses dealing with pharmacognosy and the use of nat-
or marine, in the continued search for new drugs, par-
ural products in medicine. Nevertheless, it should be of
ticularly for disease states where our present range of
valueinothercourseswherethestudyofnaturalproducts
drugs is less effective than we would wish. This is be-
is included, although the examples chosen are predomi-
ing reflected in a growing number of natural products or
nantlythosepossessingpharmacologicalactivity.
natural-product-inspired drugs entering medicine. Herbal
For centuries, drugs were entirely of natural origin
remedies are also enjoying a revival as many sufferers
and composed of herbs, animal products, and inorganic
turnawayfrommoderndrugsandembrace‘complemen-
materials.Earlyremediesmayhavecombinedtheseingre-
tary medicine’.
dients with witchcraft, mysticism, astrology, or religion,
but it is certain that those treatments that were effective
THE AIM
weresubsequentlyrecordedanddocumented,thusleading
totheearlyHerbals.Thescienceofpharmacognosy – the Manyuniversitypharmacycoursesincludeapharmacog-
knowledge of drugs – grew from these records to pro- nosycomponentcoveringastudyofplant-deriveddrugs;
vide a disciplined, scientific description of natural ma- traditionally,thisareaofnaturalproductshasbeentaught
terials used in medicine. Herbs formed the bulk of separatelyfromthemicrobiallyderivedantibiotics,orthe
these remedies. As chemical techniques improved, the animal-relatedsteroidalandprostanoiddrugs.Suchtopics
activeconstituentswereisolatedfromplants,werestruc- have usually formed part of a pharmaceutical chemistry
turally characterized, and, in due course, many were course. The traditional boundaries may still remain, de-
synthesized in the laboratory. Sometimes, more active, spite a general change in pharmacognosy teaching from
better-tolerateddrugswereproducedbychemicalmodifi- adescriptivestudytoaphytochemical-basedapproach,a
cations(semi-synthesis),orbytotalsynthesisofanalogues trendtowardsintegratingpharmacognosywithinpharma-
oftheactiveprinciples. ceutical chemistry, and the general adoption of modular
Gradually, synthetic compounds superseded many of coursestructures.Achemistry-basedteachingprogramme
the old plant drugs, though certain plant-derived agents encompassing all types of natural products of medicinal
were never surpassed and remain as valued medicines importance,semi-syntheticderivatives,andsyntheticana-
to this day. Natural drugs derived from microorganisms logues based on natural product templates is a logical
have a much shorter history, and their major impact on development. This book provides a suitable text to com-
medicine goes back only about 60 years to the intro- plement such a programme, and attempts to break down
ductionof theantibioticpenicillin.Microbiallyproduced theartificialdivisions.
Medicinal Natural Products: A Biosynthetic Approach, 3rd Edition. Paul M. Dewick
©© 2009 John Wiley & Sons, Ltd. ISBN: 978-0-470-74168-9