Carbonyls to Cancer Therapeutics

描述（由申请人提供）：过去几年来，肾癌和肝细胞癌已成为当今美国和世界面临的两个最严重的医疗问题。在过去几年中，其发病率和死亡率急剧上升-每64名男性和女性中就有1名在其生命过程中被诊断为肾癌，每125名男性和女性中就有1名在其生命过程中被诊断为肝细胞癌。在美国，据估计，每年仅用于肾癌的化疗药物就花费> 19亿美元，目前晚期肾癌或肝癌的5年存活率为10- 14%。新的、有效的化疗药物将使全世界数百万患者受益。因此，我们的长期目标是开发受天然产物启发的新型药物样小分子，可用于治疗人类癌症或作为化学探针研究治疗癌症的潜在新细胞机制。该提案的目标是我们追求这一目标的下一步，即使用有效的羰基驱动的碳-碳键形成反应合成和研究两种天然产物englerin A和psiguadial A，以及基于这些结构的药物类似物和工具化合物。对这些类似物进行严格的生物学评价将确定新的药物先导物。该提案的具体目标是：1.目的合成肾癌细胞生长抑制剂englerin A的类似物，进行构效关系和靶点鉴定研究，阐明englerins 2的作用机制。目的：完成肝癌细胞生长抑制剂psiguadial A3的合成.合成多种psiguadial A类似物，用于结构-功能和靶标鉴定研究，并阐明psiguadial的作用机制。本研究的预期结果是鉴定用于治疗人类癌症的新药先导物，开发这些化合物的有效合成，并阐明这些材料的作用机制。这些结果预计将通过提供大量这些急需的材料用于临床评价而产生积极影响。

DESCRIPTION (provided by applicant): 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.