Diversity-oriented synthesis: producing chemical tools for dissecting biology

Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar...

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Bibliographic Details
Published inChemical Society reviews Vol. 41; no. 12; pp. 4444 - 4456
Main Authors O' Connor, Cornelius J, Beckmann, Henning S. G, Spring, David R
Format Journal Article
LanguageEnglish
Published England 28.05.2012
Subjects
Animals
Biochemistry - methods
Drug Discovery - methods
functional diversity
human diseases
Humans
Mice
Models, Biological
Models, Molecular
Pharmaceutical Preparations - chemistry
Proteins - chemistry
screening
Small Molecule Libraries
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Summary:Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size. Diversity-oriented synthesis (DOS) aims to generate such structural diversity efficiently. This tutorial review has been written to introduce the subject to a broad audience and recent achievements in both the preparation and the screening of structurally diverse compound collections against so-called 'undruggable' targets are highlighted. Diversity-oriented synthesis is providing hit compounds for challenging biological targets.
Bibliography:Henning S. G. Beckmann grew up in Soest (Germany). He studied chemistry at the University of Konstanz (Germany) interrupted by a six-month internship with Aventis Pharma (Frankfurt a. M., Germany). He earned his PhD at the University of Konstanz under the supervision of Prof. Dr V. Wittmann working on chemoselective ligations and the preparation of carbohydrate arrays. In 2010 Henning joined the Spring Group at the University of Cambridge as a DAAD postdoctoral fellow, undertaking a DOS project synthesizing a library of diverse non-peptidic macrocycles.
Cornelius (Con) O' Connor grew up in Carlow, in the south east of Ireland. He obtained his B.A. (Mod.) in Chemistry in 2004 from Trinity College Dublin where he also undertook his PhD under the supervision of Dr Mike Southern, studying nucleoside mimetics and developing synthetic methodology. He subsequently joined the Connon Group at Trinity, where he worked on the development of novel catalytic systems. Con then moved to the University of Cambridge where he is currently a member of the Spring Group, researching the use of small molecules to modulate protein-protein interactions, diversity-oriented synthesis and chemical genetics.
David Spring is currently a Reader at the University of Cambridge within the Chemistry Department. He received his DPhil (1998) at Oxford University under Sir Jack Baldwin. He then worked as a Wellcome Trust Postdoctoral Fellow at Harvard University with Stuart Schreiber (1999-2001), after which he joined the faculty at the University of Cambridge. His research programme is focused on synthetic chemistry and chemical biology.
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ISSN:0306-0012
1460-4744
1460-4744
DOI:10.1039/c2cs35023h