Towards the optimal screening collection: a synthesis strategy.
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.
Nielsen
Thomas E
TE
Department of Chemistry and Chemical Biology, Harvard University, Howard Hughes Medical Institute, Cambridge, MA 02142, USA.
Schreiber
Stuart L
SL
D001671:Biochemistry / Q000379:methods / Q000639:trends; D002625:Chemistry, Organic / Q000379:methods* / Q000639:trends; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D054852:Small Molecule Libraries