This proposal represents a continuation of work initiated under NIH AREA grant CA 67236-04. 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 anti-tumor agents, multidrug resistant reversal agents, vascular disrupting agents and inhibitors of HIV integrase. These pyrrole containing natural products are usually characterized by highly oxygenated phenyl or heterocyclic groups attached at carbons 3 and 4 of the pyrrole ring system along with carbonyl containing functionality located at carbons 2 and/or 5. The synthetic methodology that we have established and are developing allows for 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 our synthetic methodology along with some new and complimentary methodology to the synthesis of the marine natural products lycogallic acid, lycogarubin B, lycogarubin C, lynamycin E and related compounds, such as new analogs of JG-03-14. JG-03-14 is an interesting synthetic pyrrole, which has emerged from our research efforts, and has demonstrated in vitro activity (IC50 of 35 nM) against breast cancer cell lines and in vivo activit against a mouse prostate cancer xenograft. JG-03-14 has also been shown to be active against drug resistant breast cancer cell lines, an inhibitor of tubulin polymerization, a vascular disrupting agent and a promoter of autophagic cell death. Our current and evolving synthetic methodologies will allow us to extend our targets to these important bioactive, natural products and new JG-03-14 analogs. All of the target molecules, their precursors and their analogs will be subject to biological evaluation by a team of highly experienced collaborators and such studies will be coupled with molecular modeling by an additional collaborator. Since our project encompasses synthesis, bioassay and molecular modeling driven SAR, we believe that a novel and viable clinical candidate for cancer chemotherapy may well emerge from such studies.
The development of new and novel chemotherapeutic agents for a particular disease state continues to depend to a significant degree on the discovery of a """"""""lead compound"""""""", which can be further developed into a viable drug candidate. Naturally occurring compounds continue to be a major source of """"""""drug leads"""""""" and our current proposal seeks to utilize our pyrrole forming reactions to synthesize biologically interesting natural products such as lycogallic acid, lycogarubins B and C, lynamycin E and related compounds. In addition to these natural product targets, we will continue to develop new derivatives of our synthetic pyrrole, JG-03-14, which continues to exhibit promising biological properties. The majority of these natural products, their analogs and precursors along with JG-03-14 analogs will be biologically evaluated and computationally modeled by a team of highly experienced collaborators.
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