Research
The Moschitto lab utilizes synthetic organic methodology to drive projects in drug discovery. Our interdisciplinary research integrates diverse synthetic methodologies—including photocatalysis, organocatalysis, and organometallic chemistry—with assay development and medicinal chemistry. Of particular interest is the ability to install covalent warheads on complex molecules and the application of covalent inhibitors in drug discovery.
- Sulfinate Protecting Groups as precursors to Sulfonyl Fluorides: The use of SFs is restricted by the methods by which they are synthesized. Most SFs are synthesized from the corresponding sulfonyl chloride, which in turn is either commercially available or made from sulfonylation under harsh, acidic conditions. Ultimately most SF containing small molecules are formed by coupling a pendant preformed SF to a core structure at the end of a synthetic sequence. This ultimately restricts the diversity in chemical structure. More useful are methods by which late stage coupling or C-H activation directly yields the SF. Our lab develops novel methods to forge new carbon-sulfur bonds on complex small molecule scaffolds. Efforts include the sulfonylation of heterocycles and arenes via a multitude of methods including photocatalysis, organometallic cross coupling, and organocatalysis.
- Our group has developed a suite of protecting groups that mask sulfonyl fluorides. These groups can be converted directly to sulfonyl fluorides with light. Our overall goal is to allow for the incorporation of sulfonyl fluorides anywhere in a synthetic endeavor. We have developed SPG libraries of small molecules that allow for coupling to a core structure followed by light mediated unmasking to form the SF.
- Accessing aryl sulfur-(VI) moieties from direct C-H sulfonylation would be an attractive method to functionalize complex molecules. We accomplish this through light mediated processes including photocatalysis and electron donor acceptor mediated complexes. Radical–radical coupling with sulfinyl radicals enables mild and practical C–S sulfonylation, and the development of various reagents that allow for C-H sulfonylation is a major goal in our laboratory. Ultimately, we seek to expand access to a variety of (hetero)arene substructures to expand chemical space.
In general, 75% of covalent inhibitors target cysteine and serine. Cysteine, however, is the least commonly found nucleophilic residue in active sites and at protein-protein interactions. On the other hand, tyrosine and lysine are more abundant, both in active sites and at protein-protein interfaces, yet the covalent warheads available to react with these residues are quite limited. SFs are one of the rare electrophilic warheads known to react with both lysine and tyrosine. Sulfonyl fluoride exchange (SuFEx), first introduced in 2014, relies upon the exchange of an incoming nucleophile with fluoride on a hexavalent sulfur forming an irreversible, covalent bond. This exchange, however, must occur under catalytic conditions whereby both the sulfonyl group and departing fluoride group are stabilized by hydrogen bonding. Given the lessened need for noncovalent interactions, covalent inhibitors such as SFs can bind effectively in shallow binding sites, thus expanding the scope of druggable/tractable targets. Our lab utilities SFs in screening and drug discovery programs to develop covalent small molecule probes and inhibitors of important biological targets.