Zipped synthesis by cross-metathesis provides a cystathionine ß-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model

Christopher D. McCune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.H. Wong, David B. Berkowitz

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine ß-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a "zipped" approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The "zipped" concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent "zipped" inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; 70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia.

Original languageEnglish (US)
Pages (from-to)242-252
Number of pages11
JournalACS Central Science
Volume2
Issue number4
DOIs
StatePublished - Apr 27 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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