DESIGN AND SYNTHESIS OF LACTONISATION BASED SCAFFOLD FOR ROS MITIGATION

Abstract

The interplay between ROS, H2S, and HNO is fundamental to cellular signalling and the preservation of redox homeostasis. Persulfides (RSSH), in particular, have emerged as superior antioxidants compared to H2S due to their enhanced nucleophilicity and ability to protect protein thiols from irreversible oxidative damage via persulfidation. However, developing chemical tools for the controlled delivery of these species remains a challenge, as many existing donors release toxic electrophilic byproducts, such as 1,4-quinone methides, which limit their biological utility. This work describes the synthesis of a stimulus-responsive scaffold for the controlled delivery of HNO and persulfides in response to hydrogen peroxide. The scaffold utilises a peroxide-activated lactonisation platform, enhanced by the Thorpe-Ingold effect, to facilitate rapid payload release while yielding a benign lactone byproduct. Central to this research is the exploration of three distinct pathways for persulfide generation: HNO-Mediated Pathway: We examine the chemical crosstalk where HNO generated forms an N-hydroxy sulfenamide intermediate by reaction with H2S, which further reacts with H2S (or thiols), generating persulfides with hydroxylamine as a byproduct. Direct Thiol-Activated Pathway: We developed a malonate diester-based donor that enables enzyme-independent persulfide release through direct activation by biological thiols. 3-MST Pathway: We use E-3MP, a well-studied compound known to be a substrate for 3-MST, as a payload. Hence, an enzyme-mediated persulfide release.