Dimuthu Vithanage

My PhD thesis is about Design, Synthesis and Reactivity Profiling of P-stereogenic Heterocycles. Organophosphorus compounds are ubiquitous in nature and have been shown to impart a wide variety of biological activities leading them to serve as novel pharmaceutical agents and biological probes. The emerging potential of electrophilic probes to serve as covalent modifiers capable of modulating protein-protein interactions, regulatory enzymes and epigenetic events, has motivated synthetic efforts to discover new probes to enable biological studies. A number of sulfur and phosphorus-based probes have emerged that exploit the innate properties of each element. Among these, P-stereogenic probes are relatively unexplored. In this regard, we have developed a modular, pot-economical and library amenable approach for the facile synthesis of P-stereogenic heterocycles. The key reactions involved in the efficient synthesis of these small molecules include a one-pot ring-closing enyne metathesis/Diels-Alder (RCEM/DA) sequence. This modular method enables access to structurally and stereochemically diverse small- to medium-sized heterocyclic phosphate analogs from easily accessible precursors. Concurrent studies are aimed at electrophilic probe development, and assessment of their reactivity patterns against biological nucleophiles in vitro, and in whole proteome screening with our collaborators using techniques such as activity-based protein profiling (ABPP) and cysteine-quantitation (Cys-Q) in order to identify critical residues in the proteome, termed “hot-spot residues”.