COMBINATORIAL DEVELOPMENT OF ANTICANCER SILATECANS

描述（改编自应用程序）：组合合成方法 将作为开发新型含硅烷喜树碱的基础 （silatecans）和相关的喜树碱，具有优化的生物学性能。 申请人将联合收割机的并行合成的能力与最近的 Curran博士实验室在喜树碱合成方法方面的创新， 高效、血液稳定和有效的抗癌药物。申请人 打算克服现有的活动被边缘化的问题， α-羟基-δ-内酯喜树碱由水解引起， 生理pH值的内酯药效团，导致形成一个 非活性羧酸盐种类。对于几种喜树碱（例如， 9-氨基喜树碱，9-硝基喜树碱），水解反应和 人血白蛋白与羧酸盐结合的能力 在患者血液中快速且基本上完全开环。进一步 使它们的临床应用复杂化的是动物的不适当性， 模型数据;活性内酯形式存在于约100倍以上 小鼠血液与人血液中的含量，由于高，物种特异性 羧酸盐形式与人白蛋白的结合。申请人将提供 有证据表明，喜树碱的A、B和E环的组合修饰 显著稳定人血液中的内酯形式。少量（3至10 mg）的约100种新的E环修饰的类似物。 对拓扑异构酶I表现出高内在效力的先导候选物， 体外对癌细胞的细胞毒效力，以及优异的人和 动物的血液稳定性与微小的种间差异，将 再合成并在荷人肝癌小鼠中进行体内疗效评价 肿瘤的 拟议商业应用：不可用

DESCRIPTION (Adapted from the application): Combinatorial synthetic methods will serve as the basis for developing novel silane-containing camptothecins (silatecans) and related camptothecins with optimized biological performance. The applicant will combine the power of parallel synthesis with recent innovations by Dr. Curran's lab in camptothecin synthetic methods to generate highly potent, blood-stable, and efficacious anticancer drugs. The applicant intends to overcome the marginalization of the activities of existing alpha-hydroxy delta-lactone camptothecins caused by the hydrolysis at physiological pH of the lactone pharmacophore, resulting in the formation of an inactive carboxylate species. For several camptothecins (e.g., 9-aminocamptothecin, 9-nitrocamptothecin), the hydrolysis reaction and the ability of human albumin to bind avidly the resulting carboxylate forms leads to a rapid and essentially complete ring opening in patient blood. Further complicating their clinical utilization is the inappropriateness of animal model data; the active lactone forms are present in some 100-fold greater amounts in mouse blood vs. human blood due to the high, species-specific binding of carboxylate forms to human albumin. The applicant will provide evidence that combined modifications in the A, B and E rings of camptothecins markedly stabilizes the lactone forms in human blood. Small quantities (3 to 10 mg) of approximately 100 novel E-ring modified analogs will be synthesized. Lead candidates displaying high intrinsic potency against topoisomerase I, high cytotoxic potencies against cancer cells in vitro, and excellent human and animal blood stabilities with insignificant interspecies variations, will be resynthesized and advanced to in vivo efficacy evaluation in mice bearing human tumors. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE