Biodiversity: New Leads for the Pharmaceutical and Agrochemical Industries (Special Publication)

324 Pages·2000·3.31 MB·English

by  Ewan J T Chrystal

Biodiversity
New Leads for the Pharmaceutical and
Agrochemical Industries
Edited by
Stephen K, Wrigley
TerraGen Discovery (UK)L td, Slough, Berkshire, UK
Martin A, Hayes
GlaxoW ellcome Research and Development,
Stevenage, Hertfordshire, UK
Robert Thomas
Biotics Ltd, Guildford, Surrey, UK
Ewan J.T. Chrystal
AstraZeneca Agrochemicals, Jeallotts Hill, Berkshire, UK
Neville Nicholson
SmithKline Beecharn, Harlow, Essex, UK
RSeC
_ -
ROYAL SOCIETY OF CHEMISTRY
The proceedings of the International Meeting Biodiversity: A Source of New Leads for the
Pharmaceutical and Agrochemical Industries held on 5-8 September 1999 at the University
of St Andrews.
Special Publication No. 257
ISBN 0-85404-830-8
A catalogue record for this book is available from the British Library
0 The Royal Society of Chemistry 2000
All rights reserved.
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Preface
The present volume is based on the proceedings of the international conference entitled
Biodiversity: A Source of New Leads for the Pharmaceutical and Agochemical
Industries held at the University of St. Andrews iaSeptember 1999. This was organised
by the Biotechnology Group of the Industrial Division of The Royal Society of
Chemistry, as was the preceding meeting on Phytochemical Diversity held at the
University of Sussex in 1996.' Whereas the primary topic of the earlier conference was
industrially useful plant products, the current volume is of wider scope and includes
substances derived from microbial, marine and plant sources.
Recent developments in genetic engineering techniques are opening up the
possibility of transferring the gene clusters responsible for the biosynthesis of individual
metabolites from any phylum to more convenient production sources, such as
microorganisms or crop plants. At the same time, advances in disease-related high
throughput screening and the combinatorial synthesis of structural analogues have
rekindled interest in examining the widest possible sources of new products. Despite the
extensive exploration of natural products throughout the past century, only a minority of
species of plants, microbes or other organisms have received more than superficial
screening. Furthermore, our understanding of structureactivity relationships is still
limited to the extent that whenever a new disease target of pharmaceutical or
agrochemical interest is developed, it is usually necessary to start screening afresh.
This book is divided into six sections comprising 21 chapters covering a wide
range of natural product topics. These are based on the individual lectures given by senior
scientists from major pharmaceutical and agrochemical companies and from academic
and government laboratories based in Australia, Brazil, Canada, the UK and the USA.
In the first section, the opening chapters review the historical development and
future potential of microbial secondary metabolites and examine novel concepts and
approaches to exploring the still largely untapped genetic resources of global
biodiversity. This section includes a timely review of past achievements and new
directions in drug discovery at the US National Cancer Institute. It also contains a
discussion of how best to deploy natural products alongside synthetic and combinatorial
chemical libraries in modern high-throughput drug discovery screens and a comparison
of the screening productivity of natural products vis-ir-vis compounds prepared by
combinatorial chemistry.
Since the development of penicillin and the subsequent launch of the antibiotic
era, the screening of microorganisms, particularly filamentous bacteria and fungi, has
dominated natural products discovery. The exploration of microbial sources of a variety
of useful new chemical entities forms the subject matter of the second section. Topics
covered include current research on drugs of both bacterial and fungal origin, ranging
from clinically-useful antifungal products to inhibitors of signal transduction and
lipoprotein-associatedp hospholipase.
iv Biodiversity: New Leads for the Pharmaceutical and Agrochemical Industries
The third section is devoted to investigations of the rapidly expanding area of
marine products as new sources of anticancer drugs and other disease-related activities. A
number of marine metabolites have been shown to exhibit intrinsically useful medicinal
properties per se or to provide valuable sources of new drug development leads. Tropical
species of marine invertebrates are described which accumulate high concentrations of
copper and zinc through the formation of complexes with cyclic peptide metabolites. In a
review of the cytotoxic dolastatins, it is demonstrated that although originally isolated
from the Indian Ocean seahare, these are actually produced by cyanobacteria and enter
the macroorganism via a dietary route.
Historically, the earliest natural products to be investigated were plant
constituents, the utilisation of which provided the principal focus of the previous
conference on Phytochemical Diversity. Special attention is devoted in the fourth section
of this volume to the exploration of regional flora, ranging from the temperate species of
the United Kingdom to the tropical rain forests of Brazil and Northern Australia. Specific
topics addressed in the opening chapter are water soluble bioactive alkaloids, whereas
other chapters examine more general aspects, including traditional plant uses,
phytomedicines and ecology-based bio-prospecting for new leads.
Two chapters in section five describe different aspects of the biosynthesis of
polyketides, which are numerically the most abundant and structurally diverse class of
natural products. The first chapter reports in vivo and in vitro studies aimed at enhancing
our understanding of the basic pathways of polyketide assembly with a view to producing
novel compounds. In the second chapter, a consistent difference in the modes of
cyclisation of the fused ring polyketides of fungi and streptomycetes is described, which
provides the basis for a new biosynthetic classification of these metabolites.
The sixth and final section is devoted to the chemical synthesis of natural products
and their derivatives. Target molecules include the strobilurin fungicides produced by
wood-rotting fungi and the events are described which led to the discovery of the
successful synthetic analogue azoxystrobin, following the synthesis of ca. 1400 separate
analogues. The final two chapters report a new strategy for the synthesis of the Prelog-
Djerassi lactonic acid, which additionally yielded unexpected products, and also the
preparation of candidate herbicides and aminoacyl tRNA synthase inhibitors modelled on
known microbial metabolites.
This compendium includes the majority of the St Andrews conference lectures,
but not the poster presentations. While some aspects of new lead discovery have
\
inevitably received more attention than have others, the editors have endeavoured to
rninimise the duplication of subject matter and to provide a balanced coverage of key
topics.
It is a particular pleasure to acknowledge the collective contributions of the
individual authors and the much valued sponsorship received from the Tony and Angela
Fish Bequest and the AstraZeneca Agrochemicals, GlaxoWellcome Research and
Development and SmithKline Beecham companies and also the assistance of the staff of
the Publications Section of The Royal Society of Chemistry in the preparation of this
volume.
May 2000 Robert Thomas
'Phytochemical Diversity: A Source of New Industrial Products, S.K. Wrigley, M.A. Hayes, R. Thomas and
E.J.T. Chrystal, (eds.), Royal Society of Chemistry, Cambridge, 1997.
Contents
1 Natural Products - History, Diversity and Discovery
Microbial Natural Products: A Past with a Future 3
A.L. Demain*
New Concepts and Approaches to Biodiversity 17
D.F . Marshall" and J.R . Hillman
Natural Products Drug Discovery at the National Cancer Institute.
Past Achievements and New Directions for the New Millennium 22
G.M Cragg", MR. Boyd, Y.F. Hallock, D.J. Newman, E.A. Sausville
and M K. Wolpert
Secondary Metabolites as a Vital Source of Animal Health Products 45
J.C . Ruddock"
The Relationship Between Natural Products and Synthetic Chemistry in
the Discovery Process 57
S. Brewer*
Natural Products vs. Combinatorials: A Case Study 66
D. Baker*, U.M ocek and C, Garr
2 Microbial Natural Products Discovery
Mushrooms, Microbes and Medicines 75
A. Buss * and M.A . Hayes
Signal Transduction Inhibitors from Microorganisms 86
S.K . Wrigley *, D.A . Kau, B. Waters and J.E . Davies
Novel Inhibitors of Lipoprotein Associated Phospholipase A2 Produced by
Pseudomonasfluorescens DSM 1 1579 100
J. Thirkettle *
3 Marine Natural Products
Marine Organisms as a Source of Novel Lead Structures for Drug
Development 113
A.E . Wrig hi *
vi Biodiversity: New Leads for the Pharmaceutical and Agrochemical Industries
The Anticancer Dolastatins as Cyanobacterial Metabolites 126
G.G. Hawigan”, H. Luesch, R.E. Moore and V.J. Paul
A Cu” Selective Marine Metabolite 140
L.A. Morris and M. Jaspars”
4 Plant Natural Products
Water Soluble Bioactive Alkaloids 169
A.A. Watson and R.J. Nash*
‘Lessons from Nature’: Can Ecology Provide New Leads in the Search for
Novel Bioactive Chemicals from Tropical Rainforests? 205
P. Reddell’ and V. Gordon
Brazilian Biodiversity: A Source of Phytomedicines, Natural Drugs and
Leads for the Pharmaceutical and Agrochemical Industries 213
B. Gilbert*
A Modern Perspective to the Traditional Use of Plants in the Highlands
of Scotland 225
R. Constadouros*
5 Biosynthesis
In Vivo and In Vitro Biosynthetic Studies: Understanding and Exploiting
Natural Pathways 233
T.J. Simpson*
Fused Ring Aromatic Polyketides are Formed by Different Cyclisation
Pathways in Fungi and Streptomycetes 249
R. Thomas*
6 Natural Products as Leads for Synthesis
The Strobilurin Fungicides - From Mushroom to Molecule to Market 277
J.M. Clough*
A Synthesis of (+)-Prelog-Djerassi Lactonic Acid 283
S.D. Hiscock, P.B. Hitchcock and P.J. Parsons*
N-(a-Aminoacyl)-5’-O-Sulfamoyladenosines:N atural Product Based
Inhibitors of Amino Acyl tRNA Synthetases 288
K. Beautemont, E.J . T. ChrystaP, J. Howard and S.M. Ridley
Subject Index 295
1 Natural Products - History, Diversity and Discovery