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Build–Couple–Transform: A Paradigm for Lead-like Library Synthesis with Scaffold Diversity

2022; American Chemical Society; Volume: 65; Issue: 16 Linguagem: Inglês

10.1021/acs.jmedchem.2c00897

1520-4804

Mélanie Uguen, Gemma Davison, Lukas J. Sprenger, James H. Hunter, Mathew P. Martin, Shannon Turberville, Jessica E. Watt, Bernard T. Golding, M.E.M. Noble, Hannah L. Stewart, Michael J. Waring,

Click Chemistry and Applications

High-throughput screening provides one of the most common ways of finding hit compounds. Lead-like libraries, in particular, provide hits with compatible functional groups and vectors for structural elaboration and physical properties suitable for optimization. Library synthesis approaches can lead to a lack of chemical diversity because they employ parallel derivatization of common building blocks using single reaction types. We address this problem through a "build-couple-transform" paradigm for the generation of lead-like libraries with scaffold diversity. Nineteen transformations of a 4-oxo-2-butenamide scaffold template were optimized, including 1,4-cyclizations, 3,4-cyclizations, reductions, and 1,4-additions. A pool-transformation approach efficiently explored the scope of these transformations for nine different building blocks and synthesized a >170-member library with enhanced chemical space coverage and favorable drug-like properties. Screening revealed hits against CDK2. This work establishes the build-couple-transform concept for the synthesis of lead-like libraries and provides a differentiated approach to libraries with significantly enhanced scaffold diversity.