“Zipped Synthesis” by Cross-Metathesis Provides a Cystathionine β‑Synthase Inhibitor that Attenuates Cellular H\u3csub\u3e2\u3c/sub\u3eS 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-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. Supplementary information (112 pp.) is attached (below)