Synthesis and evaluation of 4-(α-arylvinyl)pyridines as activated linker groups for application in antibody–drug conjugates

Andrew, Jack, Sharpe, James, Wallace, Matthew ORCID: https://orcid.org/0000-0002-5751-1827, Thirlway, Jenny, Kerigan Higgs, Patrick, Stephenson, G. Richard ORCID: https://orcid.org/0000-0003-1487-9178, Storr, Thomas and Richards, Chris ORCID: https://orcid.org/0000-0001-7899-4082 (2026) Synthesis and evaluation of 4-(α-arylvinyl)pyridines as activated linker groups for application in antibody–drug conjugates. Organic & Biomolecular Chemistry. ISSN 1477-0520

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Abstract

With the aim of increasing the cysteine-selective bioconjugation reactivity of 4-vinylpyridines, a series of 4-(α-arylvinyl)pyridines were synthesised by Suzuki–Miyaura cross-coupling of 4-(α-bromovinyl)pyridine. The rate of thia-Michael addition of cysteine-containing glutathione correlated with σx of the aryl substituent (ρ = +0.94). Introduction of electron-donating and electron-withdrawing substituents at the 3-position of 2,6-dimethyl-4-vinylpyridine all resulted in a reduction in the rate of glutathione bioconjugation, and a shift from the optimum pKa value of approximately 6–7 with the pKa values determined by pH gradient NMR titration. Potential ‘dual-armed’ 2,6-disubstituted-4-vinylpyridine antibody–drug linker groups developed previously were modified by the α-vinyl arylation methodology. This resulted in an increase in the rate of glutathione bioconjugation of approximately an order of magnitude for the p-nitrophenyl derivatives, providing opportunities for the development of new antibody–drug conjugates.

Item Type:	Article
Additional Information:	Data availability: Additional data supporting this article are available in the supplementary information (SI). Supplementary information: synthetic details, other experimental procedures, NMR spectra. See DOI: https://doi.org/10.1039/d6ob00614k.
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology Faculty of Science > School of Chemistry (former - to 2024)
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	14 Jul 2026 15:25
Last Modified:	17 Jul 2026 21:04
URI:	https://ueaeprints.uea.ac.uk/id/eprint/103848
DOI:	10.1039/d6ob00614k

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