Analytical techniques in combinatorial chemistry [Recurso electrónico] / edición, Michael E. Swartz.

Incluye referencias bibliográficas e índice.

Foreword - Gregory A. Petsko

Preface

Contributors

1. An Introduction to Combinatorial Chemistry / Harold N. Weller.--
2. The Use of Mass Spectrometry / Annette Hauser-Fang and Paul Voúros.--
3. - Infrared and Raman Spectroscopy / Hans-Ulrich Gremlich.--
4 NMR Methods / Michael J. Shapiro.--
5. The Role of Liquid Chromatography / Michael E. Swartz.--
6. Capillary Electrophoresis in Combinatorial Library Analysis / Tra S. Krull, Christina A. Gendreau, and Hong Jian Dai.--
7. Finding a Needle in a Haystack: Information Management for High-Throughput Synthesis of Small Organic Molecules / David Nickell.--
8. Bioanalytical Screening Methodologies for Accelerated Lead Generation and Optimization in Drug Discovery / James N. Kyranos and Stewart D. Chipman.--
9 Commercial Resources / Mary Brock and Mark Andrews.--

Index.

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 technique.

Chapter 1: An Introduction to Combinatorial Chemistry : The advent of combinatorial chemistry has led to a revolution in the drug discovery process, with impact on many related disciplines. Areas such as analytical chemistry, process development chemistry, and biological assay are reflecting the effects of combinatorial chemistry. However, at the same time, practitioners in those areas often have a vague idea about what combinatorial chemistry really is. Vendors of instruments and consumable supplies recognize the tremendous market potential of this new technology but are unclear about how best to capitalize on that potential. Part of the reason is that the definition of combinatorial chemistry differs from organization to organization and even within organizations depending on the specific drug discovery target. The purpose of this chapter is to provide a brief introduction to the assortment of new technologies collectively referred to as ‘‘combinatorial chemistry.’’ It will become clear that no single definition can clearly and concisely describe this new field.

Chapter 2: The Use of Mass Spectrometry : Combinatorial chemistry has evolved as a major area of interest for the pharmaceutical industry and has created a need for methods of characterization that are distinctly different from the classical tools of analytical organic chemistry like nuclear magnetic resonance (NMR) and C, H, and N analysis (1,2). There are currently several approaches for combinatorial chemistry that differ from each other in many ways (3-14). One can generate large solvated mixtures of compounds with as many as 106 different components in one sample, the so-called true libraries, or one can use the microtiter plate approach that is used to synthesize similar numbers of compounds individually on microtiter plates within small wells, so that each well contains only one or very few components. Clearly, for the second approach, synthesis and analysis must be automated to be efficient. Alternatively, many combinatorial libraries have been synthesized on solid supports (16-20) using polymeric beads. Advantages for solid phase chemistry include more efficient and simplified sample cleanup because washing of the beads usually removes all excess reagents and byproducts. This is especially true for the so-calledmix-and-split synthesis where each bead carries one component and which has been used with success by synthetic chemists. Single-bead analysis has been a good match for matrix assisted laser desorption ionization (MALDI) and several publications have shown that this approach can provide excellent data as is shown below.

Chapter 3. Infrared and Raman Spectroscopy : Since 1905, when William W. Coblentz obtained the first infrared spectrum, vibrational spectroscopy has become an important analytical tool in research and in technical fields. In the late 1960s, infrared spectrometry was generally believed to be an instrumental technique of declining popularity that was gradually being superseded by nuclear magnetic resonance (NMR) and mass spectrometry (MS) for structural determinations and by gas and liquid chromatography for quantitative analysis.

Chapter 4. NMR Methods : The realm of combinatorial chemistry is covered by a wide umbrella of techniques that include both solution phase and solid phase synthesis. The revival of solid phase synthesis has led to great interest in the development of analytical methods to monitor the reaction directly on the polymer support during the course of combinatorial syntheses. These techniques have a significant advantage compared to cleave-and-analyze characterization, particularly for optimizing reaction conditions.

Chapter 5. The Role of Liquid Chromatography : Chromatography alone, or in combination with other analytical techniques, has been used for a number of years in the drug discovery process in support of traditional organic synthesis for compound identification, compound purity and stability determinations, from lead discovery to final lead optimization, testing, and candidate selection. However, in response to increasing demands in the pharmaceutical industry to accelerate the drug discovery process and identify lead compounds in increasing numbers, new avenues of approach, such as combinatorial chemistry, must be investigated.

Chapter 6. Capillary Electrophoresis in Combinatorial Library Analysis : Although capillary electrophoresis (CE), also known as high-performance CE or HPCE, has been known and described in the literature for almost two decades, its use for combinatorial mapping is much more recent (1-14). There does not appear to be a previous review, other than that in Analytical Chemistry (an American Chemical Society journal), that describes the general applicability and applications of CE for these purposes. There are relatively few actual publications in the refereed literature that have utilized various CE modes to perform analysis of combinatorial maps.

Chapter 7. Finding a Needle in a Haystack: Information Management for High-Throughput Synthesis of Small Organic Molecules : The process of drug discovery is like searching for a needle in a haystack. Many compounds must be tested before a single marketable drug is identified. Sorting through the information generated by the discovery process is also analogous to finding a needle in a haystack. With the appropriate tools, we can improve our chance of finding the needle. It is the purpose of this paper to enhance the reader’s knowledge regarding the issues surrounding information management for high-throughput organic synthesis and to describe a hypothetical information management system.

Chapter 8. Bioanalytical Screening Methodologies for Accelerated Lead Generation and Optimization in Drug Discovery : The testing of small, synthetic organic molecules for their ability to modify the biological activity of enzymes, receptor, etc., for use as human therapeutics is the process typically referred to as drug discovery. This process has evolved significantly over the last several decades with the advent of increasingly sophisticated biological and chemical methodologies, as well as laboratory scale automation. In the first half of the twentieth century, drug discovery was primarily performed by chemists and pharmacologists. The pharmacologist's tool of choice was in vivo bioassays to test mixtures of compounds isolated from natural product sources by natural product chemists or small organic compounds that had been synthesized individually by organic chemists. The realization that protein-protein and protein-small molecule interactions transmitted information in cellular biochemical pathways was the seminal observation that led to the ‘‘lock-and-key’’ hypothesis of biomolecular interactions. This concept that the interaction of specific shapes, charges, etc., on biological molecules can serve to control cellular and organism metabolism is now well established. The discovery of small organic molecules that antagonize or agonize biochemical interactions relevant to disease processes is the goal of scientists engaged in modern drug discovery. Further advances in protein purification and structural analysis has led to an even greater understanding of these molecular recognition elements which, along with advances in computer-aided design software/hardware, has lead to the development of rational design of small organic molecules for synthesis and testing.

Chapter 9. Commercial Resources : Combinatorial chemistry and high-throughput screening (HTS) have become the fastest growth areas in pharmaceutical development. Combinatorial chemistry is a collection of technologies and disciplines. The ultimate objectives are to prepare compound libraries so that active leads can be identified more quickly, in greater numbers, and at lower costs. Over the past few years there has been an explosion in the number of companies developing, utilizing, and/ or offering the various techniques for use in the lab. Press releases announce activities in these areas on a daily basis. It is a challenge to keep up with the current players, whether they are developing or licensing proprietary technologies, establishing collaborative relationships, commercializing products, acquiring or selling business operations, or any of a number of other activities.

Área de Ciencias Básicas e Ingenierías

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