This proposal represents a continuation of work initiated under NIH AREA grant CA 67236 03. Natural products of marine origin continue to be a rich source of biologically interesting compounds and pyrrole containing marine natural products in particular have demonstrated activity as antitumor agents, multidrug resistant reversal agents and inhibitors of HIV integrase. These pyrrole containing natural products are usually characterized by highly oxygenated phenyl groups at carbons 3 and 4 of the pyrrole ring system along with carbonyl containing functionality located at carbons 2 and 5. The synthetic methodology that we have now established allows rapid construction of highly substituted and highly functionalized pyrroles. This methodology also allows for great structural diversity for structure activity relationship (SAR) studies, which could lead to chemotherapeutic agents with increased potency and decreased toxic side effects. Work proposed for the new funding cycle will involve applying this same strategy along with some new and complimentary methodology to the synthesis of marine natural products of the rigidin family (B,C and D), the ningalin family (A and C), permethyl storniamide and lamellarin G trimethyl ether. Proof of concept has recently been established for this new and complementary strategy involving 1) the application of microwave assisted Vilsmeier Haack formylation of highly substituted pyrroles and 2) the generation and base mediated cyclization of ynenoic acid amides. These methodologies, in addition to our general strategy, will allow us to extend our targets to additional important members of this ever growing class of bioactive, pyrrole containing, marine natural products. In addition to exploring these new methodologies, we will continue to evaluate new and novel analogs of our lead compound , which has already been evaluated both in vitro and in vivo against various cancer cell lines and continues to exhibit promising results (average IC50 = 62 nanomolar). All of the target molecules, their precursors and their analogs will subsequently be bioassayed by collaborators and/or the NCI. Mode of action and SAR studies will also be carried out in conjunction with our collaborators. ? ? ?
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