Solid-Phase Synthesis and Combinatorial Technologies - Hardcover

Seneci, Pierfausto

Hardcover

ISBN 10: 0471331953 ISBN 13: 9780471331957

Publisher: Wiley-Interscience, 2000

Synopsis

A unique, integrated look at solid-phase synthesis and advances in combinatorial chemistry and technologies

The last decade has seen a rapid expansion in combinatorial technologies, a field where chemistry disciplines intersect with automation, statistics, and information science, as well as certain biological disciplines. Reflecting these multidisciplinary trends, this new work provides a comprehensive overview of the most important aspects of solid-phase synthesis (SPS), combinatorial chemistry, and related combinatorial technologies. It clearly demonstrates how SPS and combinatorial chemistry have extended their application from the pharmaceutical arena to new areas, including biotechnology, material sciences, catalysis, and agrochemical industries, and explores in detail strategies for planning, designing, preparing, and testing of combinatorial libraries in various disciplines. Designed to meet the needs of both experienced combinatorial chemists and newcomers to the field, Solid-Phase Synthesis and Combinatorial Technologies:
* Surveys the most recent developments in SPS and combinatorial chemistry
* Explains the entire process, from determining the need for a library to the details necessary for synthesis of the library
* Discusses choice of format, size, and the rationale behind the design of each synthetic step
* Surveys the analytical techniques and the purification methods used to characterize and purify combinatorial libraries
* Employs a large number of examples to illustrate important concepts
* Includes problems geared toward applying acquired knowledge and designing the steps to SPS/library synthesis
* Describes the quality control and activity screening of combinatorial libraries for various applications
* Features a detailed bibliography of more than 1,700 relevant sources

About this title

About the Author

PIERFAUSTO SENECI, PhD, is Associate Director of Chemistry at the Glaxo Wellcome Medicines Research Centre, Verona, Italy.

Excerpt. © Reprinted by permission. All rights reserved.

SOLID-PHASE SYNTHESIS AND COMBINATORIAL TECHNOLOGIES

By Pierfausto Seneci

JOHN WILEY & SONS, INC.

Copyright © 2000 John Wiley & Sons, Inc.
All right reserved.
ISBN: 978-0-471-33195-7

Contents

Preface................................................................................................................................................ix1 Solid-Phase Synthesis: Basic Principles..............................................................................................................11.1 Solid Supports.....................................................................................................................................11.2 Linkers............................................................................................................................................91.3 Reaction Monitoring in Solid-Phase Synthesis.......................................................................................................261.4 Purity and Yield Determination in Solid-Phase Synthesis............................................................................................33References.............................................................................................................................................382 Solid-Phase Synthesis: Oligomeric Molecules..........................................................................................................452.1 Peptides...........................................................................................................................................452.2 Oligonucleotides...................................................................................................................................572.3 Oligosaccharides...................................................................................................................................71References.............................................................................................................................................843 Solid-Phase Synthesis: Small Organic Molecules.......................................................................................................913.1 Small Organic Molecules on Solid Phase: Target Selection and Solution Studies......................................................................923.2 Small Organic Molecules on Solid Phase: Solid-Phase Synthesis......................................................................................933.3 Small Organic Molecules on Solid Phase: From Solid-Phase Synthesis to Synthetic Organic Libraries..................................................963.4 An Example: Solid-Phase Synthesis of 1H-[2]Pyrindinones............................................................................................983.5 Solid-Phase Synthetic Strategies: Selected Examples................................................................................................107References.............................................................................................................................................1344 Combinatorial Technologies: Basic Principles.........................................................................................................1364.1 Combinatorial Technologies.........................................................................................................................1364.2 Combinatorial Libraries............................................................................................................................142References.............................................................................................................................................1625 Synthetic Organic Libraries: Library Design and Properties...........................................................................................1655.1 Primary Libraries: Shooting in the Dark?...........................................................................................................1655.2 Focused Libraries: High-Throughput Structure-Activity Relationships................................................................................1705.3 Biased-Targeted Libraries: Information-Rich Primary Libraries......................................................................................1745.4 Library Design via Computational Tools.............................................................................................................176References.............................................................................................................................................2046 Synthetic Organic Libraries: Solid-Phase Discrete Libraries..........................................................................................2106.1 Synthesis of Solid-Phase Discrete Libraries........................................................................................................2106.2 Structure Determination, Quality Control, and Purification of Solid-Phase Discrete Libraries.......................................................2156.3 Examples of Solid-Phase Discrete Library Synthesis.................................................................................................2246.4 New Trends in Solid-Phase Discrete Library Synthesis...............................................................................................246References.............................................................................................................................................2557 Synthetic Organic Libraries: Solid-Phase Pool Libraries..............................................................................................2647.1 Synthesis of Solid-Phase Pool Libraries............................................................................................................2647.2 Direct Structure Determination of Positives from Solid-Phase Pool Libraries........................................................................2797.3 Deconvolution Methods for Solid-Phase Pool Libraries...............................................................................................2907.4 Encoding Methods for Solid-Phase Pool Libraries....................................................................................................3017.5 New Trends in Solid-Phase Pool Libraries...........................................................................................................318References.............................................................................................................................................3288 Synthetic Organic Libraries: Solution-Phase Libraries................................................................................................3398.1 Solution- Versus Solid-Phase Synthetic Libraries: Which Ones to Use?...............................................................................3398.2 Solution-Phase Discrete Libraries..................................................................................................................3468.3 Purification of Solution-Phase Library Intermediates and Final Compounds: LiquidLiquid and Solid-Phase Extraction Systems.....................3618.4 Solid-Phase Assisted Solution-Phase Library Synthesis and Purification.............................................................................3728.5 Soluble Supports in Solution-Phase Combinatorial Synthesis.........................................................................................3978.6 New Trends in Solution-Phase Combinatorial Synthesis...............................................................................................404References.............................................................................................................................................4109 Applications of Synthetic Libraries..................................................................................................................4229.1 Pharmaceutical Applications........................................................................................................................4229.2 Agrochemical and Food-Related Applications.........................................................................................................4549.3 Applications to Combinatorial Reaction Optimization................................................................................................4569.4 Applications to Catalysis..........................................................................................................................4609.5 Applications to Molecular Recognition..............................................................................................................484References.............................................................................................................................................49710 Biosynthetic Combinatorial Libraries................................................................................................................50610.1 Biosynthetic Polypeptide Libraries................................................................................................................50610.2 Biosynthetic Oligonucleotide Libraries............................................................................................................53010.3 Combinatorial Biosynthesis of Natural Products....................................................................................................55210.4 Combinatorial Biocatalysis........................................................................................................................562References.............................................................................................................................................56711 Materials and Polymeric Combinatorial Libraries.....................................................................................................57911.1 Synthesis of Materials Science Libraries..........................................................................................................57911.2 Characterization and Screening of Materials Science Libraries.....................................................................................58811.3 Polymeric Combinatorial Libraries.................................................................................................................600References.............................................................................................................................................615Index..................................................................................................................................................621

Preface

During the last decade, the emergence of the so-called high-throughput screening (HTS) technique in pharmaceutical research has allowed biologists to design and set up assays, aimed toward the identification of active compounds, that can test large numbers of compounds in a short time period. Great advances in automation, information science, data management, and related disciplines have contributed to create a typical environment where every biological laboratory requires tens of thousands of compounds to be tested on several assays in a week.

The challenge represented by this phenomenon for the medicinal chemists immediately appeared too demanding if only classical organic synthesis was to be used to provide biologists with the large number of compounds they needed. The assembly of large chemical collections derived from either commercial sources or from the proprietary chemical stores of major pharmaceutical companies was used to partially fulfil these needs; however, the limitations of these collections in terms of chemical diversity and as sources of positives on different biological targets were immediately apparent.

A new discipline capable of significantly increasing the throughput of chemical synthesis in terms of diversity and numbers of biologically relevant compounds has emerged to fulfill the HTS needs. This discipline, called combinatorial chemistry, officially dates to a few key papers that appeared in the mid-1980s and since then has experienced an enormous growth and has steadily attracted the interest of many researchers, at first only in pharmaceutical research but more recently in many other disciplines.

Since the beginning, combinatorial chemistry has strongly depended on the techniques of solid-phase synthesis (SPS). For this reason a detailed presentation of solid-phase (SP) chemistry in which the differences compared to classical organic chemistry in solution are highlighted appears at the beginning of this book.

The strong involvement of many other disciplines together with chemistry in the combinatorial arena prompts the more correct definition of combinatorial technologies, in which organic, inorganic, and analytical chemistry meet automation, statistical sciences, science information, data management, and various biological disciplines with the aim of producing and testing large number of high-quality compounds for one or more specific activity. The result is the extreme acceleration of the process of discovery of active entities, and examples of the use of combinatorial technologies in various applications will be presented. The main goal of this book is to provide the reader with the general concepts related to the core aspects of combinatorial technologies, and just to mention less well established approaches that have yet to prove their worth. An integrated description of related combinatorial disciplines will provide the reader with a general multidisciplinary overview of combinatorial technologies and will hopefully be of help in understanding their enormous and still partially unexploited potential. The strengths and weaknesses of each significant approach that has appeared in the literature will be analyzed and critically discussed. Significant new trends will be presented and their possible future impact on combinatorial technologies will be analyzed.

Combinatorial technologies have been historically associated with pharmaceutical applications, and several chapters of this book are centered around this application. Several other emerging applications, though are exhaustively treated: entire chapters are dedicated to combinatorial libraries from biological sources and to inorganic or polymeric combinatorial libraries, and several sections illustrate the use of synthetic organic libraries in catalysis research, in molecular recognition, and in agricultural research among others.

This book is aimed at three main groups of readers. First, experienced combinatorial chemists and scientists will find coverage of the most recent combinatorial approaches and a detailed multidisciplinary bibliography, including more than 1700 relevant papers, reviews, books, abstracts, and patents, as well as coverage of every relevant aspect of combinatorial technologies. Second, experienced chemists who are approaching SPS and combinatorial technologies for the first time and who wish to enhance their knowledge of the area will discover the basic concepts of SPS and combinatorial chemistry and a critical evaluation of their applications to specific strategies and disciplines. This book, though, is mainly aimed at chemistry students at both graduate and postgraduate advanced course level who will find the concepts of SPS, combinatorial chemistry, and related combinatorial technologies presented in a clear and exhaustive format. The first five chapters are conceived to provide the material for a basic course on solid-phase synthesis and combinatorial technologies, with focus both on explaining the theoretical fundamentals of these disciplines and making them more obvious through many examples; appropriate citations allow the expansion of any subject according to the readers interests. The following six chapters are dedicated to an expert treatment of combinatorial technologies which hopefully covers most, if not all of the combinatorial hot topics; each of these chapters, either alone or together with several others, can represent the material for advanced, post-graduate courses. A large number of relevant examples will be thoroughly described in Chapters 6 to 11 to clarify each of the theoretical sections. The accessibility of the original papers will allow both the students to follow up an intriguing subject and their professors to expand a specific subject and to make it even more suitable for an advanced, postgraduate course.

The goal to reach such a wide and diverse audience may be overambitious, but a good blend of basic principles and detailed information about combinatorial technologies should really be useful for many workers, or future workers, in the field. The homogeneous organization of the book should also be instrumental for the reader and for the student to receive a balanced but complete over view of this new and exciting discipline and hopefully attract the attention of new talented scientists, or soon-to-be scientists, who will eventually contribute to the future development of combinatorial technologies.

Pierfausto Seneci Verona, Italy

(Continues...)

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Edition details

• Publisher: Wiley-Interscience
• Publication date: 2000
• Language: English
• ISBN 10: 0471331953
• ISBN 13: 9780471331957
• Binding: Hardcover
• Edition number: 1
• Number of pages: 656