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Build–Couple–Transform: A paradigm for lead-like library synthesis with scaffold diversity

Lookup NU author(s): Melanie Uguen, Gemma Davison, James Hunter, Dr Mathew Martin, Dr Shannon TurbervilleORCiD, Dr Jessica WattORCiD, Emeritus Professor Bernard Golding, Professor Martin NobleORCiD, Dr Hannah Stewart, Professor Mike Waring



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Uguen M, Davison G, Sprenger LJ, Hunter JH, Martin MP, Turberville S, Watt JE, Golding BT, Noble MEM, Stewart HL, Waring MJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2022

Volume: 65

Issue: 16

Pages: 11322-11339

Print publication date: 25/08/2022

Online publication date: 09/08/2022

Acceptance date: 01/08/2022

Date deposited: 17/08/2022

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.2c00897


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