Carbonyls to Cancer Therapeutics

描述（由申请人提供）：肾癌和肝细胞癌在过去几年中已经成为当今美国和世界面临的两个最严重的医疗问题。他们的发病率和死亡率在过去几年中急剧增长——每64名男性和女性中就有1人在其一生中被诊断患有肾癌，每125名男性和女性中就有1人在其一生中被诊断患有肝细胞癌。在美国，估计每年仅用于肾癌化疗的费用就高达19亿美元，目前晚期肾癌或肝癌的5年生存率为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类似药物的新小分子，这些小分子可用于治疗人类癌症，或作为化学探针来研究治疗癌症的潜在新细胞机制。这项提案的目标是我们追求这一目标的下一步，即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，利用有效的羰基驱动的碳-碳键形成反应。对这些类似物进行严格的生物学评估将发现新的药物线索。本建议的具体目的是：1。合成多种肾癌细胞生长抑制剂englerin a的类似物进行结构功能和靶点鉴定研究，阐明englerin a的作用机制2。完成肝癌细胞生长抑制剂psiguadial a3的简洁、模块化和对体选择性合成。合成多种psiguadial a类似物进行结构-功能和靶点鉴定研究，阐明其作用机制。本研究的预期成果是鉴定治疗人类癌症的新药物先导化合物，开发这些化合物的高效合成方法，阐明这些物质的作用机制。这些结果有望产生积极的影响，为临床评估提供大量急需的材料。

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.