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Library of Congress Cataloging-in-Publication Data
Dewick, Paul M. Medicinal natural products: a biosynthetic approach/Paul M. Dewick. – 3rd ed.
p. cm. Includes bibliographical references and index. ISBN 978-0-470-74168-9 (cloth) – ISBN 978-0-470-74167-2 (pbk.: alk. paper)
1. Natural products. 2. Biosynthesis. 3. Pharmacognosy. I. Title. RS160.D48 2008 615΄.3–dc22
2008044502
for Jane
CONTENTS
1
ABOUT THIS BOOK, AND HOW TO USE IT
THE SUBJECT
This book has been written primarily for pharmacy students 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 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, thus 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Gradually, synthetic compounds superseded many of the old plant drugs, though certain plant-derived agents were never surpassed and remain as valued medicines to this day.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, terrestrial or marine, in the continued search for new drugs, particularly for disease states where our present range of drugs is less effective than we would wish. This is being reflected in a growing number of natural products or natural-product-inspired drugs entering medicine. Herbal remedies are also enjoying a revival as many sufferers turn away from modern drugs and embrace ‘complementary medicine’.
THE AIM
Many university pharmacy courses include a pharmacognosy component covering a study of plant-derived drugs; traditionally, this area of natural products has been taught separately from the microbially derived antibiotics, or the animal-related steroidal and prostanoid drugs. Such topics have usually formed 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 chemistry, and the general adoption of modular course structures. A chemistry-based teaching programme encompassing all types of natural products of medicinal importance, semi-synthetic derivatives, and synthetic analogues based on natural product templates is a logical development. This book provides a suitable text to complement such a programme, and attempts to break down the artificial divisions.
THE APPROACH
This book provides 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 displays the relationships between the diverse structures encountered in nature, thus providing a rationale for natural products and replacing a descriptive approach with one based more on deductive reasoning. It also helps to transform complicated structures into a comprehensible combination of simpler fragments; natural product structures can be quite complex. Subdivision of the topics is predominantly via biosynthesis, not by 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. Lots of cross-referencing is included to emphasize links and similarities; it is not necessary to follow these to understand the current material, but they are used to stress that the concept has been met before, or that other uses will be met in due course. As important classes of compounds or drugs 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, or being tested clinically, are emphasized in the monographs by the use of bold type.
THE TOPICS
A preliminary chapter is used to outline the main building blocks, the basic construction mechanisms employed in the biosynthesis of natural products, and how metabolic pathways are deduced. Most of the fundamental principles should be familiar and will have been met previously in courses dealing with the basics of organic chemistry and biochemistry. These principles are then seen in action as representative natural product structures are described in the following chapters. The topics selected are subdivided initially into areas of metabolism fed by the acetate, shikimate, mevalonate, and methylerythritol phosphate pathways. The remaining chapters then cover alkaloids, peptides and proteins, and carbohydrates. Not all classes of natural products can be covered, and the book is intended as an introductory text, not a comprehensive reference work.
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 and materials in clinical trials.
THE FIGURES
A cursory glance through the book will show that a considerable portion of the content is in the form of chemical structures and schemes. The schemes and figures are used to provide maximum information as concisely as possible. The following guidelines should be appreciated:
FURTHER READING
A selection of articles suitable for supplementary reading is provided at the end of each chapter. In general, these are not chosen from the primary literature, but are recent review articles covering broader aspects of the topic. They are also located in easily accessible journals rather than books, and have been chosen as the most student friendly. In certain cases, the most recent reviews available may be somewhat less up to date than the information covered in this book. All of the selected articles contain information considered appropriate to this book, e.g. reviews on ‘synthesis’ may contain sections on structural aspects, biosynthesis, or pharmacology.
WHAT TO STUDY
Coverage is fairly extensive to allow maximum flexibility for courses in different institutions, and not all of 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 for 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; 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 a degree of flexibility when reading the scientific literature, and to appreciate that science is always changing.
WHAT TO LEARN
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, whilst the names of chemicals and the enzymes involved in the pathways are even less relevant and included only for information; it is the mechanistic explanations that 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. There is no alternative to memory for some of the material covered in the monographs, if it is required; 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.
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 their right to name the compound. The organism in which the compound is found is frequently chosen to supply the root name, e.g. hyoscyamine from Hyoscyamus, atropine from Atropa, or penicillin from Penicillium. 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 (ammes).
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. Homo- is used to indicate one carbon more, whereas nor- means one carbon less. The position of this change is then indicated by systematic numbering of the carbon chains or rings. Some groups of compounds, such as steroids, fatty acids, and prostaglandins, are named semi-systematically from an accepted root name for the complex hydrocarbon skeleton. 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 should be regarded as more pertinent than the names used.
It will soon become apparent that drug names chosen by pharmaceutical manufacturers are quite random, and in most cases have no particular relationship to the chemical structure. However, some common stems are employed to indicate relationship to a group of therapeutically active drugs. Examples are -cillin for antibiotics of the penicillin group, cef- for antibiotics of the cephalosporin group, -mycin for antibiotics produced by Streptomyces , -caine for local anaesthetics, -stat for enzyme inhibitors, -vastatin for HMGCoA reductase inhibitors, prost for prostaglandins, and gest for progestogens. We are also currently still in a transitional period during which many established drug names are being changed to recommended international non-proprietary names (rINNs); both names are included here, with the rINN preceding the older name.
CONVENTIONS REGARDING ACIDS, BASES, AND IONS
In many structures, the abbreviation OP is used to represent the phosphate group and OPP the diphosphate (or pyrophosphate) group:
At physiological pH values, these groups will be ionized as shown, but in schemes where structures are given in full, the non-ionized 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 acids are shown in non-ionized form, although they will typically exist as zwitterions:
Ionized and non-ionized 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.
SOME COMMON ABBREVIATIONS
| 5-HT | 5 -hydroxy tryptamine |
| ACP | acyl carrier protein |
| ADP | adenosine diphosphate |
| Ara | arabinose |
| ATP | adenosine triphosphate |
| B: | general base |
| CoA | coenzyme A as part of a thioester, e.g. acetyl-CoA (CH3COSC0A) |
| Dig | digitoxose |
| DMAPP | dimethylallyl diphosphate (dimethylallyl py- rophosphate) |
| DXP | 1-deoxyxylulose 5-phosphate |
| Enz | enzyme (usually shown as thiol: EnzSH) |
| FAD | flavin adenine dinucleotide |
| FADH2 | flavin adenine dinucleotide (reduced) |
| FAS | fatty acid synthase |
| FH4 | tetrahydrofolic acid |
| FMN | flavin mononucleotide |
| FMNH2 | flavin mononucleotide (reduced) |
| FPP | farnesyl diphosphate (farnesyl pyrophos- phate) |
| Fru | fructose |
| GABA | y-aminobutyric acid |
| Gal | galactose |
| GFPP | geranylfarnesyl diphosphate (geranylfarne- syl pyrophosphate) |
| GGPP | geranylgeranyl diphosphate (geranylgeranyl pyrophosphate) |
| Glc | glucose |
| GPP | geranyl diphosphate (geranyl pyrophos- phate) |
| HA | general acid |
| HSCoA | coenzyme A |
| IPP | isopentenyl diphosphate (isopentenyl py- rophosphate) |
| LT | leukotriene |
| Mann | mannose |
| MEP | methylerythritol phosphate |
| MVA | mevalonic acid |
| NAD+ | nicotinamide adenine dinucleotide |
| NADH | nicotinamide adenine dinucleotide (reduced) |
| NADP+ | nicotinamide adenine dinucleotide phos- phate |
| NADPH | nicotinamide adenine dinucleotide phos- phate (reduced) |
| NRPS | non-ribosomal peptide synthase |
| 0 | oxidation - in schemes |
| P | phosphate - in text |
| P | phosphate - in structures |
| PCP | peptidyl carrier protein |
| PEP | phosphoenolpyruvate |
| PG | prostaglandin |
| PKS | polyketide synthase |
| PLP | pyridoxal 5’-phosphate |
| PP | diphosphate (pyrophosphate) - in text |
| PP | diphosphate (pyrophosphate) - in structures |
| Rha | rhamnose |
| Rib | ribose |
| SAM | S-adenosyl methionine |
| TPP | thiamine diphosphate (thiamine pyrophos- phate) |
| TX | thromboxane |
| UDP | uridine diphosphate |
| UDPGlc | uridine diphosphoglucose |
| UTP | uridine triphosphate |
| W-M | Wagner-Meerwein (rearrangement) |
| Xyl | xylose |
| Δ | heat |
| hv | electromagnetic radiation; usually UV or visible |
FURTHER READING
Pharmacognosy, Phytochemistry, Natural Drugs
Books
Bruneton J (1999)Pharmacognosy, Phytochemistry and Medicinal Plants. Lavoisier , Paris.
Evans WC (2001)Trease & Evans’ Pharmacognosy. Saunders , London.
Heinrich M, Barnes J, Gibbons S and Williamson EM (2004)Fundamentals of Pharmacognosy and Phytotherapy. Churchill Livingstone , London.
Samuelsson G (2004)Drugs of Natural Origin. A Textbook of Pharmacognosy . Swedish Pharmaceutical Press, Stockholm.
Reviews
Baker DD, Chu M, Oza U and Rajgarhia V (2007) The value of natural products to future pharmaceutical discovery. Nat Prod Rep 24, 1225-1244.
Bode HB and Miiller R (2005) The impact of bacterial genomics on natural product research. Angew Chem Int Ed 44,6828-6846.
Butler MS (2004) The role of natural product chemistry in drug discovery. J Nat Prod 67, 2141-2153; errata (2006) 69, 172. Butler MS (2008) Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep 5, 475-516.
Chin Y-W, Balunas MJ, Chai HB and Kinghorn AD (2006) Drug discovery from natural sources. AAPS J 8, 239-253.
Espin JC, Garcia-Conesa MT and Tomas-Barberan FA (2007) Nutraceuticals: facts and fiction. Phytochemistry 68 2986-3008.
Kennedy J (2008) Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosyn thetic engineering for diversifying natural products. Nat Prod Rep 25, 25-34.
McChesney JD, Venkataraman SK and Henri JT (2007) Plant natural products: back to the future or into extinction? Phytochemistry 68, 2015-2022.
Misiek M and Hoffmeister D (2007) Fungal genetics, genomics, and secondary metabolites in pharmaceutical sciences. Planta Med 73, 103-115.
Newman DJ (2008) Natural products as leads to potential drugs: an old process or the new hope for drug discovery? J Med Chem 51, 2589-2599.
Newman DJ and Cragg GM (2004) Marine natural products and related compounds in clinical and advanced preclinical trials. J Nat Prod 67, 1216-1238.
Newman DJ and Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70, 461-477.
Phillipson JD (2007) Phytochemistry and pharmacognosy. Phytochemistry 68, 2960-2972.
Tietze LF, Bell HP and Chandrasekhar S (2003) Natural product hybrids as new leads for drug discovery. Angew Chem Int Ed 42, 3996-4028.