Synthesis of vinaxanthone analogs
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Spinal cord injury is a debilitating injury that affects 12,000 people in the U.S. annually.1 Current treatment is limited; research in tissue engineering, biomaterials, and gene therapy have dominated neuroregeneration studies. However, an inadequate amount of attention has been dedicated to the development of small molecule therapeutics. Vinaxanthone (SM-345431) and xanthofulvin (SM-216289) are two novel small molecule compounds co-isolated from Penicillium sp. SPF-3059 that demonstrate axonal regenerative properties in both C. elegans and adult rats. Initially, the molecules were thought to inhibit semaphorin 3A, a protein which induces the collapse of neuronal growth cones. Knockout studies of semaphorin 3A indicate that simply shutting off inhibitory signaling does not equate to the pronounced neuroregeneration present from vinaxanthone and xanthofulvin administration, suggesting that the molecules possess alternative modes of action. To uncover the mechanism of action for these two small molecules, analogs of vinaxanthone and xanthofulvin are being developed for structure-activityrelationship studies in C. elegans. Further research into the action of these analogs will provide useful information regarding CNS inhibitory signaling in spinal cord injury models and potential therapeutic options. Currently, the synthesis of vinaxanthone analogs is being pursued. Initial data from G-protein coupled receptor assays (GPCR) indicates that various vinaxanthone analogs have been found to possess either positive or negative allosteric modulation for the succinate receptor 1 protein (SUCNR1 or GPR91). The synthesis of more vinaxanthone analogs will be pursued (with an envisioned vinaxanthone library of 64 compounds) and their biological activity tested.