Mantilla, B.S., White, J.S., Mosedale, W.R.T. et al. (4 more authors) (2024) Discovery of Trypanosoma brucei inhibitors enabled by a unified synthesis of diverse sulfonyl fluorides. Communications Chemistry, 7. 237. ISSN 2399-3669
Abstract
Sets of electrophilic probes are generally prepared using a narrow toolkit of robust reactions, which tends to limit both their structural and functional diversity. A unified synthesis of skeletally-diverse sulfonyl fluorides was developed that relied upon photoredox-catalysed dehydrogenative couplings between hetaryl sulfonyl fluorides and hydrogen donor building blocks. A set of 32 diverse probes was prepared, and then screened against Trypanosoma brucei. Four of the probes were found to have sub-micromolar anti-trypanosomal activity. A chemical proteomic approach, harnessing an alkynylated analogue and broad-spectrum fluorophosphonate tools, provided insights into the observed anti-trypanosomal activity, which likely stems from covalent modification of multiple protein targets. It is envisaged that the unified diversity-oriented approach may enable the discovery of electrophilic probes that have value in the elucidation of biological and biomedical mechanisms.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Funding Information: | Funder Grant number EPSRC (Engineering and Physical Sciences Research Council) EP/N025652/1 EPSRC (Engineering and Physical Sciences Research Council) EP/W002914/1 Leverhulme Trust RPG-2018-030 |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Oct 2024 09:34 |
Last Modified: | 11 Dec 2024 14:59 |
Status: | Published online |
Publisher: | Nature Research |
Identification Number: | 10.1038/s42004-024-01327-8 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:218525 |