Swartz Analytical Techniques in Combinatorial Chemistry

the early successes of the combinatorial approach. Combinatorial chemistry has many guises. In its purest form it involves the synthesis of all possible compounds from a set of modular building blocks. However, it can also mean high-throughput parallel synthesis of individual pure compounds, simultaneous synthesis of mixtures of compounds free in solution or on solid support, or a number of other variations on these themes. Regardless of the details of the process, the objective is the same: to produce a large number of chemically ‘‘diverse’’ compounds as rapidly as possible.

And that it does. Combinatorial methods have rewriten the standards for synthetic productivity. Until about 10 years ago, a good chemist could make and characterize perhaps 50 compounds per year. A combinatorial chemist aims for more like 50,000. Such numbers define a revolution, one that has already transformed the pharmaceutical industry and is likely to eventually make an impact on every other area of industrial chemistry. Analytical chemistry is no exception, which brings us to the subject of this splendid book.

It is, of course, one thing to make 50,000 compounds and quite another to know what one has made. Yet that is essential, because when new molecules are available in such staggering numbers chemistry has become an information science. Consider a chemically ‘‘diverse’’ (whatever that means, and nobody really knows yet) library of 50,000 compounds. Now screen that against, say, 50 different drug targets. Then imagine that you don’t know what any of the compounds are. The ones that give ‘‘hits’’ in your assays won’t remain unknown for long: you will purify those and characterize them. Yet in doing so, you will throw information away. If you knew the structure of every compound, then the ones that failed in your assays would be almost as valuable to you as the ones that succeeded because they would define the chemical types that were not likely to work for that particular set of target classes. Combinatorial chemistry promises to provide structure and activity data on a scale never before imagined, but it will do so only if one can characterize what one makes.

The task for the analytical community, then, is to develop methods of separating and characterizing compounds suitable for the assembly-line scale of combinatorial chemistry. This book details the methods currently available and also discusses emerging techniques that could have a major impact. It covers the gamut from a concise introduction to the various methods of combinatorial synthesis (Weller) to a splendidly useful compendium of commercial resources (Brock and Andrews). In between, we are taken through clear and critical descriptions of mass spectrometry (Vouros and Hauser-Fang), I-R (Gremlich), and NMR (Shapiro) methods for high-throughout compound identification, including the difficulties inherent in dealing with mixtures of

compounds that most combinatorial synthetic strategies produce. Detailed consideration of the mixture problem is the basis for subsequent chapters on chromatography (Swartz) and capillary electrophoresis (Krull, Gendreau, and Dai). The latter process is of particular interest because it is so open to miniaturization, and there seems little doubt that the laboratory of the future will eventually be on a chip. The remaining chapters treat the informationexplosion problem head-on. Nicell discusses techniques for managing the reams of data that an analytical lab will face when it deals with combinatorial libraries, and Kyranos and Chipman outline the various ways of screening libraries in a high-throughput fashion. Although the focus of the book is on analytical techniques, these latter chapters in particular make it an excellent introduction to the entire field of combinatorial chemistry.

It’s funny how the wheel comes around for scientific disciplines. At just about the time that chemistry as a whole, and perhaps analytical chemistry in particular, was being written off by some as a ‘‘mature field’’ unlikely to produce the kind of cutting-edge excitement of, say, neurobiology or human genetics, along comes combinatorial chemistry. The making, and characterizing, of molecules has once again been thrust into the heart of things, where it has been for almost 200 years. If we are living in the Information Age, then surely it is appropriate that the Central Science should become at last an information science. This book is a manifesto for the next Chemical Revolution.

Gregory A. Petsko

Gyula and Katica Tauber Professor of Biochemistry

Director, Rosenstiel Basic Medical Sciences Research Center

Brandeis University

Waltham, Massachusetts

Analytical Techniques in Combinatorial Chemistry is intended to provide specific details on how analytical techniques are brought to bear on the unique challenges presented in the combinatorial chemistry laboratory. It is aimed primarily at industrial and pharmaceutical chemists faced with the task of developing methods, analyzing the results, and documenting and/or managing the discovery process in a combinatorial setting. Since many major pharmaceutical companies are in the process of staffing combinatorial chemistry departments, this publication could also serve as a training and reference source, or perhaps a graduate-level textbook. While the book is not intended to be an exhaustive literature review, specific citations are examined that highlight the use of analytical techniques and the way in which they are utilized to solve the unique problems encountered. It presents a basic introduction to the field for a novice, while providing detailed information sufficient for an expert in a particular analytical techique.

In closing, I would like to thank several colleagues who have contributed to my efforts in the burgeoning field of drug discovery and combinatorial chemistry. They include Bob Pfeifer, Beverly Kenney, Bob Karol, Ray Crowley, Pat Fowler, Mike Balogh, John Hedon, and Eric Block of Waters Corporation (Milford, Massachusetts) as well as Steve Preece, Mark McDowall, and Andrew Brailsford of Micromass Limited (Manchester, United Kingdom). Special thanks also go to Carol, Kristina, and Robert of MCS (Uxbridge, Massachusetts) for their help and consideration in the preparation of this text.

Michael E. Swartz

8.Bioanalytical Screening Methodologies for Accelerated Lead