Medicinal Natural Products

A Biosynthetic Approach

Paul M. Dewick

• Publisher: Wiley
• Year: 2011
• Print ISBN: 9780470741672, 9780470741689
• eBook ISBN: 9781119964575
• Edition: 3
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

Medicinal Natural Products: A Biosynthetic Approach, Third Edition, provides a comprehensive and balanced introduction to natural products from a biosynthetic perspective, focussing on the metabolic sequences leading to various classes of natural products. The book builds upon fundamental chemical principles and guides the reader through a wealth of diverse natural metabolites with particular emphasis on those used in medicine.

There have been rapid advances in biosynthetic understanding over the past decade through enzymology, gene isolation and genetic engineering. Medicinal Natural Products has been extended and fully updated in this new edition to reflect and explain these developments and other advances in the field. It retains the user-friendly style and highly acclaimed features of previous editions:

• a comprehensive treatment of plant, microbial, and animal natural products in one volume
• extensive use of chemical schemes with annotated mechanistic explanations
• cross-referencing to emphasize links and similarities
• boxed topics giving further details of medicinal materials, covering sources, production methods, use as drugs, semi-synthetic derivatives and synthetic analogues, and modes of action

Medicinal Natural Products: A Biosynthetic Approach, Third Edition, is an invaluable textbook for students of pharmacy, pharmacognosy, medicinal chemistry, biochemistry and natural products chemistry.

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:

• A figure may present a composite scheme derived from studies in more than one organism.
• Comments in italics provide an explanation in chemical terms for the biochemical reaction; detailed enzymic mechanisms are not usually considered.
• Schemes in separate frames show a mechanism for part of the sequence, the derivation of a substrate, or perhaps structurally related systems.
• Although enzymic reactions may be reversible, sin­gle rather than reversible arrows are used, unless the transformation is one that may be implicated in both directions, e.g. amino acid/keto acid transaminations.
• El, E2, etc., refer to enzymes catalysing the transforma­tion, when known. Where no enzyme is indicated, the transformation may well have been determined by other methodology, e.g. isotope tracer studies. Speculative conversions may be included, but are clearly indicated.
• Enzyme names shown are the commonly accepted names; in general, only one name is given, even though alternative names may also be in current use.
• Proteins identified via the corresponding gene are often assigned a code name/number by researchers, and no systematic name has been proposed. This means that proteins carrying out the same transformation in differ­ent organisms may be assigned different codes.
• Double-headed curly arrows are used to represent an addition-elimination mechanism as follows:

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 ...

Table of contents

• Cover
• Title Page
• Copright
• Dedication
• 1: ABOUT THIS BOOK, AND HOW TO USE IT
• 2: SECONDARY METABOLISM: THE BUILDING BLOCKS AND CONSTRUCTION MECHANISMS
• 3: THE ACETATE PATHWAY: FATTY ACIDS AND POLYKETIDES
• 4: THE SHIKIMATE PATHWAY: AROMATIC AMINO ACIDS AND PHENYLPROPANOIDS
• 5: THE MEVALONATE AND METHYLERYTHRITOL PHOSPHATE PATHWAYS: TERPENOIDS AND STEROIDS
• 6: ALKALOIDS
• 7: PEPTIDES, PROTEINS, AND OTHER AMINO ACID DERIVATIVES
• 8: CARBOHYDRATES
• INDEX