Stimuli responsive small molecule persulfidating agents

Abstract

Hydrogen sulfide H2S plays an integral role in several intracellular signaling processes modulating an array of physiological functions including vasodilation neurotransmission antioxidant response inflammation angiogenesis hypoxia sensing to list a few One of the widely accepted mechanisms of H2S signaling is the oxidative post translational modification of cysteine residues in proteins known as protein persulfidation While H2S can persulfidate proteins only under oxidizing conditions persulfides and polysulfides collectively termed as sulfane sulfurs can modify proteins directly and are more efficient than H2S Additionally low molecular weight LMW persulfides are better reductants and multiple evidences suggest that persulfides are far superior at sequestering oxidants compared to its congeners thiols and H2S Hence small molecule persulfides have emerged as important intermediates in combating oxidative and electrophilic stress This has fueled the development of strategies to enhance cellular persulfides and modulate the levels of intracellular protein persulfidation LMW persulfides are unstable in aqueous solution due to its propensity to undergo disproportionation therefore generating these species in cells has been a major challenge In this regard we designed two distinct strategies for the generation of persulfides The first strategy involved design and synthesis of prodrugs of persulfides wherein the persulfide moiety is masked by a protecting group which can be cleaved in response to an external stimulus Any diseased condition is often accompanied by an overproduction of free radicals and reactive oxygen species ROS So we synthesized and evaluated a persulfide prodrug responsive to hydrogen peroxide H2O2 a stable ROS The compound upon activation by H2O2 was found to generate persulfides and exhibit cytoprotective effects in cells against oxidative stress induced damage The next class of prodrugs were designed to be activated by the enzymes b glycosidase which are upregulated in cells exposed t