Conceptual and technological advances in chemistry and biology have transformed the drug discovery process. Evolutionary pressure among the diverse scientific and engineering disciplines that contribute to the identification of biologically active compounds has resulted in synergistic improvements at every step in the process. Exploiting Chemical Diversity for Drug Discovery encompasses the many components of this transformation and presents the current state-of-the-art of this critical endeavour. From the theoretical and operational considerations in generating a collection of compounds to screen, to the design and implementation of high-capacity and high-quality assays that provide the most useful biological information, this book provides a comprehensive overview of modern approaches to lead identification. Beginning with an introductory overview, subsequent chapters address topics that include the design of chemical libraries and methods for optimizing their diversity; automated and accelerated chemistry; high throughput assay design and detection techniques; and strategies for data analysis and property optimization. Written by experts in the field, both academic and industrial, and illustrated in full colour, this book provides an excellent overview for current practitioners and will also serve as a stimulating resource for future generations. Researchers in organic and medicinal chemistry, the biological and pharmacological sciences, as well as those interested in allied computational and engineering disciplines will value the comprehensive and up-to-date coverage.
Exploiting Chemical Diversity for Drug Discovery
By Paul A. Bartlett, Michael EntzerothThe Royal Society of Chemistry
Copyright © 2006 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-842-7Contents
Section 1 Operational Developments in Chemistry,
Chapter 1 The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds Steven V. Ley, Mark Ladlow and Emma Vickerstaffe, 3,
Chapter 2 Accelerated Chemistry: Microwave, Sonochemical, and Fluorous Phase Techniques Kristofer Olofsson, Peter Nilsson and Mats Larhed, 33,
Section 2 Conceptual Advances in Synthesis: "Prospecting" – Design of Discovery Libraries and the Search for Hits,
Chapter 3 Biosynthesis of "Unnatural" Natural Products Yi Tang and Chaitan Khosla, 57,
Chapter 4 Combinatorial Synthetic Design: The Balance of Novelty and Familiarity A. Ganesan, 91,
Chapter 5 Compound Collections: Acquisition, Annotation, and Access Reg Richardson, 112,
Chapter 6 Chemical Diversity: Definition and Quantification Alan C. Gibbs and Dimitris K. Agrafiotis, 137,
Section 3 Conceptual Advances in Synthesis: "Mining" – Turning a Hit into a Lead,
Chapter 7 Focused Libraries: The Evolution in Strategy from Large-Diversity Libraries to the Focused Library Approach Ruben Tommasi and Ivan Cornella, 163,
Chapter 8 Translating Peptides into Small Molecules Gerd Hummel, Ulrich Reineke and Ulf Reimer, 184,
Section 4 Operational Developments in Screening and High Throughput Assays,
Chapter 9 High-Density Plates, Microarrays, Microfluidics Christof Fattinger and Gregor Dernick, 203,
Chapter 10 Fluorescence Technologies for the Investigation of Chemical Libraries Eric Trinquet and Gérard Mathis, 233,
Chapter 11 The Use of Genetically Engineered Cell-Based Assays in in-vitro Drug Discovery Renate Schnitzer and Wolfgang Sommergruber, 247,
Chapter 12 NMR-Based Screening: A Powerful Tool in Fragment-Based Drug Discovery Jochen Klages, Murray Coles and Horst Kessler, 263,
Chapter 13 Screening Chemical Microarrays: Methods and Applications Pappanaicken R. Kumaresan and Kit S. Lam, 291,
Section 5 Conceptual Advances in Lead Evaluation: Screen Early and Often,
Chapter 14 Screen/Counter-Screen: Early Assessment of Selectivity Martyn N. Banks, Litao Zhang and John G. Houston, 315,
Chapter 15 Concepts for In Vitro Profiling: Drug Activity, Selectivity and Liability Michael B. Bolger, Robert Fraczkiewicz, Michael Entzeroth and Boyd Steere, 336,
Chapter 16 In Silico Surrogates for In Vivo Properties: Profiling for ADME and Toxicological Behavior Michael B. Bolger, Robert Fraczkiewicz and Boyd Steere, 364,
Chapter 17 Uses of High Content Screening in Chemical Optimization Francesca Casano, Zhuyin Li and Tina Garyantes, 386,
Subject Index, 405,
CHAPTER 1
The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds
STEVEN V. LEY, MARK LADLOW AND EMMA VICKERSTAFFE
1 Introduction
In recent years, the drug discovery process has been revolutionised by progress in the areas of proteomics and genomics, together with advances in high-throughput screening (HTS) of compounds for activity in various biological assays. This in turn has created a much higher demand for the rapid production of novel and functionally diverse compounds, thereby driving chemists to look for new ways to simplify, expedite and automate the process of organic synthesis. The importance of synthe-sising high-quality arrays of discrete compounds, from which meaningful structure activity relationships can be derived and also act as assets for future screening protocols is now well recognised.
The origins of high-throughput organic chemistry can be traced back to the work of Merrifield who pioneered solid-phase peptide synthesis. The development of this approach enabled the subsequent automation of peptide synthesis. Early attempts at high-throughput chemistry utilised this strategy, exploiting the advantages of solid-phase chemistry, which facilitates reaction work-up and rapid sample processing.
Today, although solid-phase organic synthesis (SPOS) remains a powerful technique for some aspects of high-throughput chemistry, there are a number of limitations that restrict its application. For example, while in some instances, by-product formation on the resin can be monitored without cleavage from the resin, separation of these materials from the desired product is not feasible until the end of the reaction sequence. The consequences are often cumulative, resulting in a complex final purification step. Additionally, even though a number of well-established methods for monitoring resin-bound intermediates have been developed, accurate quantitative measurement of immobilised material still represents a major challenge. Techniques such as magic angle spinning (MAS)-NMR and IR enable the analysis of molecules covalently bound to the resin, whereas MS techniques or the use of analytical constructs, require that the analyte be cleaved from the resin. The development of new chemistry on the solid support is therefore difficult and often protracted, requiring extended reaction rehearsal and optimisation.
Although SPOS is well suited to the synthesis of large, but relatively simple compound libraries, typically using combinatorial methods, the time required for route development and limitations as to the synthetic transformations that can be reliably performed is often restrictive. Increasingly, therefore, higher quality, smaller arrays are being synthesised by employing a much wider range of precedented solution-phase chemistries. Historically, attempts to increase the throughput of solution-phase chemistries have been confounded by the need for extensive work-up and purification procedures. An increasingly popular approach to circumvent many of these drawbacks involves the use of supported reagents." In this way, the advantages of performing chemistry in solution, namely, straightforward reaction monitoring and optimisation, are maintained. Excess reagents and their associated by-products may be readily separated from the desired solution-phase reaction product by simple filtration. A wide variety of reagents and scavenger resins have been developed in recent years to extend the scope of this new paradigm.
The concept of a reagent being immobilised on a solid-support was first exploited in catalytic applications as early as 1946. However, it was not until the end of the twentieth century that solid-supported nucleophiles and electrophiles immobilised on a polystyrene (PS) support were applied to the rapid purification of compounds prepared using standard solution-phase procedures. This application and its subsequent extension to the immobilisation of reagents has stimulated an explosion in the number of publications describing the development of novel polymer-bound reagents, catalysts and scavengers. As an ever-increasing number of these reagents becomes commercially available, interest in applying polymer-assisted solution-phase (PASP) techniques within industrial settings escalates.
PASP synthesis can be divided into two main approaches; these being (a) the use of supported reagents and scavengers, and (b) the adoption of a catch-and-release strategy (Figure 1). Both of these techniques allow the production of clean products, without the need to resort to traditional purification techniques, such as column...
