title: "Zipped Synthesis" by Cross-Metathesis Provides a Cystathionine β-Synthase Inhibitor that Attenuates Cellular H2S Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model.
abstract: The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-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-C 2-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 SH-SY5Y 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.
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: McCune
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117597.
authors.forename: Su Jing
authors.initials: SJ
authors.lastname: Chan
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Beio
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: Weijun
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Chung
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Szczesniak
authors.affiliation: Neurodegeneration Research Laboratory, National Neuroscience Institute , Singapore 308433.
authors.forename: Chou
authors.initials: C
authors.lastname: Chai
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117597.
authors.forename: Shu Qing
authors.initials: SQ
authors.lastname: Koh
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117597.
authors.forename: Peter T-H
authors.initials: PT
authors.lastname: Wong
authors.affiliation: Department of Chemistry, University of Nebraska , Lincoln, Nebraska 68588, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Berkowitz