Cyclic Thiosulfinates and Cyclic Disulfides Selectively Cross-Link Thiols While Avoiding Modification of Lone Thiols.
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...
| Published in: | Journal of the American Chemical Society Vol. 140; no. 24; pp. 7377 - 7381 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Article |
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American Chemical Society
6/20/2018
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| Subjects: | |
| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=130322001&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 130322001 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 6/20/2018 vid: 140 iid: 24 pid: 997 pub: American Chemical Society artinfo: ui: 130322001 10.1021/jacs.8b01136 ppf: 7377 ppct: 4 formats: tig: atl: Cyclic Thiosulfinates and Cyclic Disulfides Selectively Cross-Link Thiols While Avoiding Modification of Lone Thiols. aug: au: Donnelly, Daniel P. Dowgiallo, Matthew G. Salisbury, Joseph P. Aluri, Krishna C. Iyengar, Suhasini Chaudhari, Meenal Mathew, Merlit Miele, Isabella Auclair, Jared R. Lopez, Steven A. Manetsch, Roman Agar, Jeffrey N. affil: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States Barnett Institute of Chemical and Biological Analysis, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States su: Disulfides Thiols Superoxide dismutase Lipoic acid Density functional theory sug: subj: Disulfides Thiols Superoxide dismutase Lipoic acid Density functional theory ab: 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. Thiolatedirected 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 new rate-determining step, ring cleavage. Our calculations suggest that the origin of accelerated ring cleavage is improved frontier molecular orbital overlap in the thiolate-disulfide interchange transition. Five- to seven-membered cyclic thiosulfinates were synthesized and efficiently cross-linked up to 10-fold faster than their cyclic disulfide precursors; functioned in the presence of biological concentrations of glutathione; and acted as cell-permeable, potent, tolerable, intracellular cross-linkers. This new class of thiol cross-linkers exhibited click-like attributes including, high yields driven by the enthalpies of disulfide and water formation, orthogonality with common functional groups, water-compatibility, and ring strain-dependence. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2018 holdings: @attributes: islocal: N |
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