Synthetic and computational studies on liphagal: a natural product inhibitor of PI-3K

The natural product liphagal has been shown to function as a reasonably potent and selective inhibitor of the key signaling enzyme PI-3Kα. We have been interested in developing an analog class of PI-3K inhibitors based upon this unusual terpenoid natural product. Toward that end, we have evaluated the binding of the natural product to its target protein computationally and formulated a class of simplified analogs based on the structural analysis. Utilizing the cycloadduct derived from tetrabromocyclopropene and furan, we were able to generate a key, versatile scaffold upon which to pursue this analog design.