The continuing quest for new drugs and agrochemicals has seen researchers looking to the natural world for potential products. Plants and microorganisms have long been investigated as sources of new lead compounds, but the scope of this book has been widened to include substances derived from marine organisms. Advances in genetic engineering, high throughput screening and structure elucidation have also opened up further avenues for exploration. Competitive pressure from the field of combinatorial chemistry has expedited new approaches to natural product analysis and stimulated debate on the industrial utilization of natural products. Biodiversity: New Leads for the Pharmaceutical and Agrochemical Industries reviews and discusses aspects of modern natural products research. The central theme of many articles is the sustainable use of global biodiversity. Microbial, plant and marine products are presented as the sources of new drugs, including antifungal products, antibiotics, anticancer agents and animal health products. There is also coverage of the biosynthesis of polyketides and the chemical synthesis of natural products and their derivatives. A unique blend of industrial and academic perspectives on the importance of biodiversity and natural products, this book will prove an important source of state-of-the-art information for researchers, teachers and graduates in the chemical and biological sciences.
Biodiversity
New Leads for the Pharmaceutical and Agrochemical Industries
By Stephen K. Wrigley, Martin A. Hayes, Robert Thomas, Ewan J.T. Chrystal, Neville NicholsonThe Royal Society of Chemistry
Copyright © 2000 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-830-4Contents
1 Natural Products – History, Diversity and Discovery,
Microbial Natural Products: A Past with a Future A.L. Demain, 3,
New Concepts and Approaches to Biodiversity D.F. Marshall and J.R. Hillman, 17,
Natural Products Drug Discovery at the National Cancer Institute Past Achievements and New Directions for the New Millennium G.M. Cragg, M.R. Boyd, Y.F. Hallock, D.J. Newman, E.A. Sausville and M.K. Wolpert, 22,
Secondary Metabolites as a Vital Source of Animal Health Products J.C. Ruddock, 45,
The Relationship Between Natural Products and Synthetic Chemistry in the Discovery Process S. Brewer, 57,
Natural Products vs. Combinatorials: A Case Study D. Baker, U. Mocek and C. Garr, 66,
2 Microbial Natural Products Discovery,
Mushrooms, Microbes and Medicines A. Buss and M.A. Hayes, 75,
Signal Transduction Inhibitors from Microorganisms S.K. Wrigley, D.A. Kau, B. Waters and J.E. Davies, 86,
Novel Inhibitors of Lipoprotein Associated Phospholipase A2 Produced by Pseudomonas fluorescens DSM 11579 J. Thirkettle, 100,
3 Marine Natural Products,
Marine Organisms as a Source of Novel Lead Structures for Drug Development A.E. Wright, 113,
The Anticancer Dolastatins as Cyanobacterial Metabolites G.G. Harrigan, H. Luesch, R.E. Moore and V.J. Paul, 126,
A Cu2+ Selective Marine Metabolite L.A. Morris and M. Jaspars, 140,
4 Plant Natural Products,
Water Soluble Bioactive Alkaloids A.A. Watson and R.J. Nash, 169,
'Lessons from Nature': Can Ecology Provide New Leads in the Search for Novel Bioactive Chemicals from Tropical Rainforests? P. Reddell and V. Gordon, 205,
Brazilian Biodiversity: A Source of Phytomedicines, Natural Drugs and Leads for the Pharmaceutical and Agrochemical Industries B. Gilbert, 213,
A Modern Perspective to the Traditional Use of Plants in the Highlands of Scotland R. Constadouros, 225,
5 Biosynthesis,
In Vivo and In Vitro Biosynthetic Studies: Understanding and Exploiting Natural Pathways T.J. Simpson, 233,
Fused Ring Aromatic Polyketides are Formed by Different Cyclisation Pathways in Fungi and Streptomycetes R. Thomas, 249,
6 Natural Products as Leads for Synthesis,
The Strobilurin Fungicides – From Mushroom to Molecule to Market J.M. Clough, 277,
A Synthesis of (+)-Prelog-Djerassi Lactonic Acid S.D. Hiscock, P.B. Hitchcock and P.J. Parsons, 283,
N-(α-Aminoacyl)-5'-O-Sulfamoyladenosines: Natural Product Based Inhibitors of Amino Acyl tRNA Synthetases K. Beautemont, E.J.T. Chrystal, J. Howard and S.M. Ridley, 288,
Subject Index, 295,
CHAPTER 1
Natural Products – History, Diversity and Discovery
MICROBIAL NATURAL PRODUCTS: A PAST WITH A FUTURE
Arnold L. Demain
Fermentation Microbiology Laboratory, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
For over 50 years, antibiotics have served us well in combating infectious bacteria and fungi. The recently increased development of resistance to older antibacterial and antifungal drugs is being challenged by (i) newly discovered antibiotics (e.g., pneumocandins), (ii) new semi-synthetic versions of old antibiotics (e.g., glycylcyclines), (iii) older underutilized antibiotics (e.g., teicoplanin), and (iv) new derivatives of previously undeveloped narrow-spectrum antibiotics (e.g., streptogramins, everninomycin). Many of these products are in late stage clinical testing at the moment. In addition, many antibiotics are used commercially, or are potentially useful, in medicine or agriculture for activities other than their antibiotic action. They are used as antitumor agents, enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, and anti-migraine agents, in medicine. Agricultural products include bioherbicides, antiparasitic agents, bioinsecticides and growth promotants for animals (especially ruminants) and plants. A number of these products were first discovered as mycotoxins, or as antibiotics which failed in their development as such. Combinatorial chemistry will accelerate the discovery of new derivatives of natural products. It will join structure-function drug design, semi-synthesis, and recombinant DNA technology as techniques complementing the screening of natural products.
1 INTRODUCTION
Natural products have been an overwhelming success in our society. The doubling of our life span in the twentieth century has been attributed to the use of plant and microbial secondary metabolites. These have reduced pain and suffering, and revolutionized medicine by allowing for the transplantation of organs. Natural products are the most important anticancer and anti-infective agents. Over 60% of approved and pre-NDA candidates are either natural products or related to them, not including biologicals such as vaccines and monoclonal antibodies. Almost half of the best selling pharmaceuticals are natural or are related to natural products. Often, the natural molecule has not been used itself but served as a lead molecule for manipulation by chemical or genetic means.
Secondary metabolism has evolved in nature in response to needs and challenges of the natural environment. Nature has continually carried out its own version of combinatorial chemistry for the period of over 3 billion years during which bacteria have inhabited the earth. During that time, there has been an evolutionary process in progress in which producers of secondary metabolites evolve according to their local environments. If the metabolites are useful to the organism, the biosynthetic genes are retained and genetic modifications further improve the process. Combinatorial chemistry practiced by nature is much more sophisticated than combinatorial chemistry in the laboratory, yielding exotic structures rich in stereochemistry, concatenated rings and reactive functional groups. As a result, an amazing variety and number of products have been found in nature. The total number of natural products produced by plants has been estimated to be over 500,000. About 100,000 secondary metabolites of molecular weight less than 2500 have been characterized, mainly produced by microbes and plants: some 50,000 are from microorganisms. The enormous diversity existing in secondary metabolism can be illustrated by the following two examples.
(i) 22,000 terpenoids have been described from living organisms. They are all produced from hydroxymethylglutaryl coenzyme A via mevalonate. Their structures contain repeats of the five-carbon isoprene unit unless subsequently modified. Their functions include intercellular communication in animals (steroid hormones) and in plants (gibberellins), aroma (volatile terpenoids), pigments (carotenoids) and sexual hormones in animals and fungi. There are 86 known gibberellins, of which 26 are produced by fungi and the rest by plants.
(ii) 10,000 polyketides are known, most of which are produced by bacteria and fungi. These include antibiotics (e.g., erythromycin, tetracyclines, rifamycins), antitumor agents (e.g., doxorubicin, daunorubicin, enediynes), immunosuppressants (e.g., FK 506, rapamycin), antiparasitic agents (e.g., avermectins), antifungals (e.g.,...
