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 Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the internet at http://dnb.ddb.de ISBN 978-3-7643-8098-4 Birkhäuser Verlag AG, Basel – Boston – Berlin The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad- casting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. © 2008 Birkhäuser Verlag AG Basel · Boston · Berlin P.O. Box 133, CH-4010 Basel, Switzerland Part of Springer Science+Business Media Printed on acid-free paper produced from chlorine-free pulp. TCF ∞ Cover design and layout: Micha Lotrovsky, CH-4106 Therwil, Switzerland Printed in Germany ISBN 978-3-7643-8098-4 e-ISBN 978-3-7643-8117-2 9 8 7 6 5 4 3 2 1 www.birkhauser.ch 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 vii 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