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Scope of on-DNA nucleophilic aromatic substitution on weakly-activated heterocyclic substrates for the synthesis of DNA-encoded libraries

Lookup NU author(s): Dr Isaline Castan, 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

DNA-Encoded Libraries (DEL) represent a promising hit finding strategy for drug discovery. Nonetheless, the available DNA-compatible chemistry remains of limited scope. Nucleophilic aromatic substitution (SNAr) has been extensively used in DEL synthesis but has generally been restricted to highly activated (hetero)arenes. Herein, we report an optimised procedure for of the SNAr reaction through the use of factorial experimental design (FED) on-DNA using 15% THF as a co-solvent. This method gave conversions of >95% for pyridine and pyrazine scaffolds for 36 secondary cyclic amines. This analysis provides a new DNA-compatible SNAr reaction to produce high yielding libraries. The scope of this reaction on other amines is described. This work identifies challenges for the further development for DNA-compatible SNAr reactions.

Publication metadata

Author(s): Castan IFSF, Madin A, Pairaudeau G, Waring MJ

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry

Year: 2022

Volume: 63

Print publication date: 01/06/2022

Online publication date: 25/03/2022

Acceptance date: 23/02/2022

Date deposited: 24/02/2022

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.bmc.2022.116688

DOI: 10.1016/j.bmc.2022.116688

ePrints DOI: 10.57711/wpg6-w178

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