Design Synthesis and Evaluation of Bioactivable Organic Donors of Sulfur Dioxide

Abstract

Sulfur dioxide (SO2) is colourless, pungent gas and has long been considered as a toxic pollutant but has recently emerged as a possible mediator of cellular signaling. SO2 is widely used as a food preservative and as an antibacterial agent in winemaking. SO2 is produced endogenously by metabolism of sulfur-containing amino acids and by oxidation of H2S. In aqueous media, SO2 gets hydrated forms sulfite and bisulfite. In order to study physiological roles of SO2, typically inorganic or organic sources of SO2 are used. To investigate precisely several untapped roles of SO2 in biological system, tools that generate SO2 inside cell in a reliable and controllable manner are needed. Hitherto, few chemical tools have been known to generate SO2 and they all have certain limitations that we proposed to address. Our lab for the very first time previously has reported thiol activated SO2 donors and their biological activity against Mycobacterium tuberculosis (Mtb). Structural modifications for thiol activated SO2 donors led us to a new set of compounds that were excellent inhibitors of Staphylococcus aureus (S.aureus). Together, we have developed chemical tools for SO2 donation based on diverse activation mechanisms with potential applications as antibacterials. Next, we describe efforts towards the new and improved SO2 donors. First, we designed and synthesized a series of esterase-sensitive SO2 donors. These compounds undergo self-immolation to generate SO2 upon exposure to esterase, an enzyme that is widely prevalent in cells. Using this design as a prototype, we next directed the delivery of SO2 to bacteria using the bacterial enzyme nitroreductase. The strategy was adapted to co-deliver SO2 and a clinically used antibiotic. In this strategy we presented the design and synthesis of a nitroreductase stimuli specific fluoroquinolone conjugated novel class of prodrugs. In this approach, we synthesized theranostic prodrug of ciprofloxacin as therapeutic with coumarin fluorophore for real-time monitoring for drug release.