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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

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


Abstract

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

URL: https://doi.org/10.1021/acs.jmedchem.2c00897

DOI: 10.1021/acs.jmedchem.2c00897


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