Carbonyls to Cancer Therapeutics

描述(申请人提供)：肾癌和肝细胞癌在过去的几年里已经成为美国和当今世界面临的两个最严重的医学问题。在过去的几年里，他们的发病率和死亡率急剧上升--有1名男性和女性在其一生中被诊断为肾癌，每125名男性和女性中有1名在其一生中被诊断为肝细胞癌。在美国，估计每年花费19亿美元用于肾癌的化疗，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球数百万患者受益。因此，我们的长期目标是开发受天然产品启发的新的类药物小分子，这些小分子可用于治疗人类癌症，或用作化学探针，研究潜在的治疗癌症的新细胞机制。这项提议的目标是我们追求这一目标的下一步，即利用高效的羰基驱动的碳-碳键形成反应，合成和研究两种天然产物--英格列林A和Psiguadial A，以及基于这些结构的类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估将确定新的药物线索。本研究的具体目标是：1.合成多种肾癌细胞生长抑制因子Englerin A的类似物，用于结构-功能和靶标鉴定研究，阐明Englerins的作用机制；2.完成肝癌细胞生长抑制因子Psiguadial A的简明、模块化和对映选择性合成；3.合成多种Psiguadial A类似物，用于结构-功能和靶标鉴定研究，阐明Piguadial A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化合物，开发这些化合物的有效合成方法，并阐明这些物质的作用机制。预计这些结果将通过为临床评估提供大量这些急需的材料而产生积极影响。

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.