Development of Small Molecule Radiation Sensitizers

The goal of this aim is to develop an ENOX1 inhibitor that is active in the nM range. An iterative approach will be used. Using the current lead compound as a scaffold, new derivatives will be synthesized and chemically characterized. Specifically, a series of indole analogs structurally related to our lead compound will be synthesized and characterized using 1H and 13C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectroscopy analysis, and elemental combustion analysis. The synthesis will be performed by the medicinal chemistry group in my laboratory. Once synthesized and characterized, the compounds will sent by mail to Drs. Freeman and Konjeti for testing. Drs Crooks, Konjeti, and Freeman will communicate on a weekly basis via email and phone and compound will be subjected to structure-activity studies; synthesizing and systematically modifying structural moieties, quantitatively evaluating a compound's ability to inhibit ENOX1. The quantitative results from each assay will be used to establish a rank order of biological activity. As this information becomes available, it will be used to guide the synthesis of new compounds.