Towards the Optimal Screening Collection: A Synthesis Strategy

• Published in: Angewandte Chemie International Edition Vol. 47; no. 1; pp. 48 - 56
• Main Authors: Nielsen, Thomas E, Schreiber, Stuart L
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 2008; WILEY-VCH Verlag; WILEY‐VCH Verlag
• Subjects: Biochemistry - methods; Biochemistry - trends; build/couple/pair; Chemistry, Organic - methods; Chemistry, Organic - trends; diversity-oriented synthesis; molecular diversity; Molecular Structure; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; small molecules; Stereoisomerism; synthesis design
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.200703073

The development of effective small-molecule probes and drugs entails at least three stages: 1) a discovery phase, often requiring the synthesis and screening of candidate compounds, 2) an optimization phase, requiring the synthesis and analysis of structural variants, 3) and a manufacturing phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in-house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small-molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning. Therefore, a challenge for synthetic chemistry is to develop a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases. Although this transformative chemistry remains elusive, progress is being made. Herein, we review a newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve these challenging goals.