Renal and hepatocellular cancers have emerged over the past several years as two of the most critical medical problems facing the United States and the world today. Their rates of incidence and mortality have grown dramatically over the past several years - 1 in 64 men and women will be diagnosed with renal cancer over the course of their lives, and 1 in 125 men and women will be diagnosed with hepatocellular cancer over the course of their lives. In the United States, it is estimated that >$1.9 billion is spent annually o chemotherapeutics for renal cancer alone, and the current 5-year survival rates for late stage kidney or liver cancer are 10-14%. New, effective chemotherapeutics will benefit millions of patients worldwide. Therefore, our long-term goal is to develop new drug-like small molecules inspired by natural products that can be used for the treatment of human cancer or as chemical probes to study potentially new cellular mechanisms for the treatment of cancer. The objective of this proposal is our next step in pursuit of that goal, which is the synthesis and study of two natural products, englerin A and psiguadial A, as well as drug-like analogs and tool compounds based on these structures using efficient carbonyl-driven carbon-carbon bond forming reactions. Rigorous biological evaluation of these analogs will identify new drug leads.
The specific aims of this proposal are: 1. To synthesize a variety of analogs of the renal cancer cell growth inhibitor englerin A for structure-function and target identification studies and elucidate the mechanism of action of the englerins 2. To complete a concise, modular, and enantioselective synthesis of the hepatoma cell growth inhibitor psiguadial A 3. To synthesize a variety of analogs of psiguadial A for structure-function and target identification studies and elucidate the mechanism of action of the psiguadials The expected outcome of this research is the identification of new drug lead leads for the treatment of human cancers, the development of efficient syntheses of these compounds, and the elucidation of the mechanism of action of these materials. These results are expected to have a positive impact by providing quantities of these much-needed materials for clinical evaluation.
This proposal is an exploration of compounds as potential chemotherapeutic drug leads inspired by two new natural products with promising biological activity. The proposal leverages the inherent topology of these natural products and the reactivity bestowed upon organic molecules by the carbonyl function.
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