Natural Compounds as Drugs Volume I

379 Pages·2008·3.621 MB·English

by  Mark S. Butler, David J. Newman (auth.), Frank Petersen, René Amstutz (eds.)

Progress in Drug Research
Founded by Ernst Jucker
Series Editors
Prof. Dr. Paul L. Herrling Alex Matter, M.D., Director
Novartis International AG Novartis Institute for Tropical Diseases
CH-4002 Basel 10 Biopolis Road, #05-01 Chromos
Switzerland Singapore 138670
Singapore
Progress in Drug Research
Natural Compounds
as Drugs
Volume I
Vol. 65
Edited by
Frank Petersen and René Amstutz
Birkhäuser
Basel Boston Berlin
• •
Editors
Frank Petersen
René Amstutz
Novartis Pharma AG
Lichtstrasse 35
4056 Basel
Switzerland
Library of Congress Control Number: 2007934728
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Contents
Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Glossar. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Mother nature’s gifts to diseases of man: The impact of natural
products on anti-infective, anticholestemics and anticancer
drug discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Mark S. Butler and David J. Newman
Drug discovery and development with plant-derived
compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Olivier Potterat and Matthias Hamburger
Evolutionary mechanisms underlying secondary metabolite
diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Holger Jenke-Kodama, Rolf Müller and Elke Dittmann
Biodiversity, chemical diversity and drug discovery. . . . . . . . . . . . 141
Sheo B. Singh and Fernando Pelaez
High impact technologies for natural products screening. . . . . . . 175
Frank E. Koehn
Virtual screening for the discovery of bioactive natural
products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Judith M. Rollinger, Hermann Stuppner and Thierry Langer
Strain improvement for production of pharmaceuticals and
other microbial metabolites by fermentation . . . . . . . . . . . . . . . . . 251
Arnold L. Demain and Jose L. Adrio
v
Table of contents
Nutritional and engineering aspects of microbial process
development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Prakash S. Masurekar
Natural products from plant cell cultures. . . . . . . . . . . . . . . . . . . . . . 329
Elizabeth McCoy and Sarah E. O’Connor
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
vi
Foreword
The use of herbal medicines, their preparation and application in human
therapy, was described for the first time in history by the Sumerians
approximately 5000 years ago. Even earlier in India and China, a highly
sophisticated medical system with plant-based therapies had been devel-
oped. Along with the rise of the later empires, this knowledge was further
expanded and institutionalized, while moving westwards to Egypt, Greece,
and to the Arabic world, having a considerable influence on human ther-
apy – until today.
Not all of these traditional medicines, although partially in medical
practice still today, can be considered as efficacious or useful according
to Western therapeutic standards, often due to the fact that the tradi-
tional disease categories cannot be easily translated into the “language”
of Western medicine. The identification of active principles from plant
preparations often failed, as the biological activity could not be enriched.
However, there are numerous examples like morphine, quinine, salicylic
acid, rivastigmine, digitalis glycosides, reserpine, or artemisinine, where
the correlation between plant extract and the modern medicine, based on
a single entity drug, was successfully established. All of these natural prod-
ucts originated from traditional medical practice and opened the door to
today’s medical indication areas, fundamentally enriching our knowledge
of the pathophysiology and underlying biochemistry of diseases.
The successful market introduction of a drug requires a continuous
financial engagement over approx. 12 years and finally an investment of
US $ 1 to 1.5 billion, including capital costs. Although these figures steeply
increased during the last decade and continue to follow this trend, the
success of the pharmaceutical industry as mirrored in the numbers of filed
new molecular entities (NMEs) and the development of new therapies for
unmet medical needs can be considered at best modest. The investments
during the last 15 years in innovative technologies like the “omics” world
for target finding, target validation and the strongly improved capabilities
to populate the chemical space by combinatorial concepts, still need to
deliver on the financial figures.
During the same time period, research in natural products has largely
been abandoned in drug discovery and development, mainly by the US
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Foreword
American and British pharmaceutical industry, and has been reduced in
almost all other companies – at a first glance for some good reasons.
The molecules from nature are a weak starting point in today’s high
throughput screening and lead development processes. The extremely time-
sensitive process from uHTS, the capability to validate millions of com-
pounds on a given target and the identification of suitable starting points
for medicinal chemists was squeezed together to a few weeks. Natural prod-
ucts were hardly adjustable to these new principles of lead identification.
They are tested either as enriched mixtures, whereby the identification
of the biologically active compound is achieved in intolerably repetitive
and cumbersome process steps, or as pure compounds, often limited with
respect to numbers and amounts. The vast majority of the natural products
in the screening libraries are mainly singletons, unsuited for any hit explo-
sion efforts. The chemical complexity of a natural product hampers also
the engagement of medicinal chemists in industry. Synthetic molecules are
often understood as a more auspicious alternative to reach the number of
derivatives, as defined and accordingly rewarded in a project-driven indus-
trial environment. A HTS campaign yields a variety of synthetic compound
families interacting with the target of interest. Therefore a structure-activity
relationship is immediately available with the submission of a hit list.
There are, however, solid arguments to leverage the molecules from
nature in drug discovery. Besides the impressive success story in the phar-
maceutical industry, natural products cover a unique breadth of biologi-
cally functionalized, complementary chemical diversity in comparison
to other library types, are still sources for new pharmacophore classes, or
represent a promising starting point to intervene with protein-protein
interactions, to mention only a few opportunities to address current areas
of pressing need in drug discovery.
With the books Natural Products as Drugs Vol I and II we aim to show not
only the complex technology catalogue applicable to natural products in
drug development-related science. Important additional motivations for
the current edition have been to demonstrate how natural products can
successfully be integrated in most technologies and concepts of modern
drug discovery and to illustrate their potential for innovative treatments
of human diseases.
The chapters cover topics from applied biodiversity considerations in
natural products discovery, screening concepts, dereplication technologies
viii
Foreword
to the fermentation aspects of microbially and plant-derived secondary
metabolites, conditiones sine qua non. These proven technologies require
experts in ecology, botany, microbiology, genetics, physiology, fermenta-
tion technologies, chemistry, etc. to be effective and successful in the search
for new drugs from nature. New developments and understandings thus
contribute to an improved economy of the natural products deliverable in
industrial research, the “magic triangle” of “faster, quicker, cheaper”.
Efficient physiological investigations aiming at titer improvement of a
microbially or plant-derived natural product or the generation of further
derivatives play an essential role in avoiding a shortage in supply, often a
motivation to disregard natural products in the lead selection discussions.
Without a reliable and efficient supply of sufficient material, the prospects
of natural products will be compromised and consequently, they will be
uncoupled from the quickly emerging and pursued new directions in the
science of drug discovery.
We compiled recent developments in the understanding of genetics
principles, how nature created the generally accepted broad coverage of
chemical space, and in the deciphering of silent gene clusters. Both research
directions allow us an in-depth insight into the genetic organization of
biosynthetic genes, generating new opportunities in pathway engineering
to enlarge chemical diversity by biosynthetic manipulations.
Furthermore, the systematic application of whole animals such as
zebrafish or yeast mutants as phenotype screens in combinations with
biochemical approaches is increasingly used for target or pathway identi-
fication. This fascinating new avenue in drug discovery should improve
the classical limitations of secondary metabolites, phenotypic activity of
unknown underlying mechanisms of action, and will ultimately attract
more medicinal chemists.
In the last years, natural products have been mainly omitted from
virtual screening, due to their complexity, the frequent lack of exact ste-
reochemical description, or insufficient computing power. However, more
and more scientists from academia find ways out of these initial restric-
tions and successfully apply natural products to the development of new
pharmacophore models.
The diversity of natural products is increasingly used as examples to
generate “natural product-like” libraries. Herewith, the inclusion of natu-
ral products in cheminformatics investigations is essential to understand
ix
Foreword
underlying principles of structural characteristics of natural products. The
interpretation of these analyses yields new ideas to mimic arrangements,
combinations, and chemistry of functionalities of a natural product, repre-
senting a fascinating new facet in most recent chemical library design.
It is a surprising and encouraging phenomenon that even after their
relegation in big pharma, many new drugs or drug candidates still origi-
nate from natural products or derivatives thereof. We count an impressive
number of new clinical candidates and an almost stable number of patent
applications over the years (Nature Reviews Drug Discovery March 2005,
volume 5), contradicting the general notion of their non-druglike features
and confirming that natural products are exempt from the Ro5, as repeat-
edly communicated by Chris Lipinsky.
The edition Natural Products as Drugs is concluded with dedicated mono-
graphs of natural products or compounds based on them, representing
potential or already proven ways for innovative medical intervention.
Hence most recent enabling technologies and innovative chemical
derivation concepts have substantially changed the classical natural prod-
ucts research during the last decade, giving us new possibilities to exploit
the huge diversity designed and generated by nature, of which only the tip
of the iceberg seems to have been discovered yet. Natural products expand
the molecular armamentarium for therapeutic choices and may improve
the moderate success of today’s applied chemical diversity. Together with
the understanding of their target proteins, they offer chances of comple-
mentary routes in drug discovery, great opportunity to better understand
the causality of diseases, and will ultimately lead to new drugs for medical
needs.
We are grateful to Birkhäuser Verlag for editing this volume. We also
wish to acknowledge the excellent cooperation with Beatrice Menz, Anke
Brosius, and Yvonne Schlereth for their assistance and seamless coordina-
tion. Most importantly, we would like to thank all chapter authors for their
enthusiasm in the idea of the book, for their valuable time and knowing
patience.
Frank Petersen
René Amstutz
x