SYNTHESIS OF BRIDGED HETROCYCLIC ANTITUMOR AGENTS

桥联杂环抗肿瘤剂的合成

• 批准号: 3165070
• 负责人: ANDREW S KENDE
• 金额: $ 11.49万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-15 至 1995-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165070
• 关键词: alkaloids; antineoplastics; beta lactam antibiotic; bridged cyclic compound; chemical addition; drug design /synthesis /production; heterocyclic compounds; heterocyclic polycyclic compound; macrolide antibiotics; molecular rearrangement; monoterpenes; stereochemistry

The long-term objective of our research are to discover new chemical strategies and tactics for the synthesis of complex natural products. Our focus is on the synthesis of molecules known or likely to have in vivo anticancer activity. We propose to carry out the first type synthesis of two such substances. One such target is the ansa-macrolide pyrandione antibiotic Lankacidin C, reported to have good in vivo antitumor activity in mice bearing L1210 leukemia, 6C3HED/OG lymphosarcoma and B16 melanoma. We propose an enantiospecific approach based on the intramolecular rearrangement of an enantiopure beta-lactam intermediate, a reaction already demonstrated in our laboratory during the previous grant period. Our second target molecule is the C35H47O9N oxazole polyene ansa-macrolide rhizoxin. This complex, polyfunctional molecule shows high in vivo activity against L1210 and P388 leukemia and B16 melanoma in mice, and against certain vincristine- and andriamycin-resistant tumor lines. Recent studies suggest that rhizoxin and some of its congeners are potent inhibitors of microtubule assembly, with a receptor binding mechanism somewhat resembling that of maytansine. Our proposed synthesis is enantiospecific and highly convergent, so as to provide maximum modular flexibility for structural modifications and analog synthesis. The proposed target molecules will serve as demanding frameworks to test a variety of new, chemoselective and stereoselective synthetic methodologies. These include the use of novel functionalized and sometimes chiral vinylstannane nucleophiles, development of vinylogous beta-ketophosphonate dianons or their equivalents as bifunctional lynch- pin reagents, enantioselective constructions of polyfunctional lactones, an enantioselective Darzens condensation and stereoselective elaboration of an oxazoletriene chromophore. Advanced intermediates and new analogs of the two target molecules, uniquely accessible by our synthetic protocols, will be screened for antineoplastic activity. Structural modifications observed to enhance potency will be further investigated to generate therapeutically improved drugs based on these two frameworks.

我们研究的长期目标是发现新的化学物质 复杂天然产物合成的策略和策略。 我们的 重点是体内已知或可能存在的分子的合成 抗癌活性。 我们建议进行第一类合成 两种这样的物质。 其中一个目标是 ansa-macrolide 吡喃二酮 抗生素兰卡西丁 C，据报道具有良好的体内抗肿瘤活性 患有 L1210 白血病、6C3HED/OG 淋巴肉瘤和 B16 黑色素瘤的小鼠。 我们提出了一种基于分子内对映体特异性的方法 对映体纯 β-内酰胺中间体的重排，反应 已经在我们的实验室在上一个资助期间进行了演示。 我们的第二个目标分子是 C35H47O9N 恶唑多烯 ansa-macrolide 根毒素。 这种复杂的多功能分子在体内表现出高 对小鼠 L1210 和 P388 白血病以及 B16 黑色素瘤的活性，以及 对抗某些长春新碱和安霉素耐药的肿瘤系。 最近的研究表明根瘤菌素及其一些同源物是有效的 微管组装抑制剂，具有受体结合机制 有点类似于美登素。 我们建议的合成是 对映体特异性和高度收敛性，从而提供最大的模块化 结构修饰和模拟合成的灵活性。 所提出的目标分子将作为测试的严格框架 各种新型化学选择性和立体选择性合成 方法论。 其中包括使用新颖的功能化和 有时是手性乙烯基锡烷亲核试剂，发展插烯 β-酮膦酸二农或其等价物作为双功能林奇- pin 试剂、多官能内酯的对映选择性结构、 对映选择性 Darzens 缩合和立体选择性阐述 恶唑三烯发色团。 高级中间体和新类似物 两个目标分子，可以通过我们的合成方法独特地获得 方案，将筛选抗肿瘤活性。 结构性 将进一步研究观察到的增强效力的修饰 基于这两个框架产生治疗改进的药物。