Cyclic Thiosulfinates and Cyclic Disulfides Selectively Cross-Link Thiols While Avoiding Modification of Lone Thiols

Journal of the American Chemical Society
Daniel P DonnellyJeffrey N Agar

Abstract

This work addresses the need for chemical tools that can selectively form cross-links. Contemporary thiol-selective cross-linkers, for example, modify all accessible thiols, but only form cross-links between a subset. The resulting terminal "dead-end" modifications of lone thiols are toxic, confound cross-linking-based studies of macromolecular structure, and are an undesired, and currently unavoidable, byproduct in polymer synthesis. Using the thiol pair of Cu/Zn-superoxide dismutase (SOD1), we demonstrated that cyclic disulfides, including the drug/nutritional supplement lipoic acid, efficiently cross-linked thiol pairs but avoided dead-end modifications. Thiolate-directed nucleophilic attack upon the cyclic disulfide resulted in thiol-disulfide exchange and ring cleavage. The resulting disulfide-tethered terminal thiolate moiety either directed the reverse reaction, releasing the cyclic disulfide, or participated in oxidative disulfide (cross-link) formation. We hypothesized, and confirmed with density functional theory (DFT) calculations, that mono- S-oxo derivatives of cyclic disulfides formed a terminal sulfenic acid upon ring cleavage that obviated the previously rate-limiting step, thiol oxidation, and accelerated the n...Continue Reading

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Citations

Aug 15, 2020·Biochemical Society Transactions·Gareth S A Wright
Jun 25, 2021·Chemical Science·Yangyang ChengStefan Matile
Jun 5, 2020·The Journal of Organic Chemistry·Peng QiHongguang Du
Sep 2, 2021·JACS Au·Quentin LaurentStefan Matile

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