Design and Development of Enzyme Triggered Persulfide Donors

Abstract

Persulfides are known to mediate certain crucial functions in sulfur mediated redox processes and as significant counterparts in cellular signaling. They have been known to evoke distinct and extensive physiological changes. Protein-persulfidation is recognized as a major pathway for signal transduction and is one of the mechanisms by which persulfide exerts its effects on physiological systems. It protects the proteins from deleterious effects of oxidants, thus sustaining their structure and function. Hence, inducing persulfidation has possible therapeutic uses. Lack of trigger-specific persulfide donor scaffolds that results in controlled release of discrete persulfide species on demand has led to the poor understanding of the persulfide chemistry and redox biology. The need for further investigation about their potential functioning led us to design and develop a triggerable persulfide donor. In this project we aim to design a persulfide donor, which upon activation by specific enzyme as stimulus, releases the desired persulfide (RSSH) species. Reported here is the design and synthesis of β- glucosidase triggered donors for N-acetylcysteine (NAC) persulfide and benzyl persulfide which are characterized by NMR, HRMS and IR spectroscopy. The sugar trigger groups and the NAC-SSH leaving group are hypothesized to increase the permeability, solubility and biocompatibility of the molecule respectively, indispensable to mention the release of fairly innocuous byproduct. The future prospect of the project involves studying the release rates of persulfides from the compounds as well as performing their cytotoxicity assays.