SYNTHESIS OF BRIDGED HETEROCYCLIC ANTITUMOR AGENTS

桥联杂环抗肿瘤剂的合成

• 批准号: 2086729
• 负责人: ANDREW S KENDE
• 金额: $ 11.71万
• 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/2086729
• 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战略和战术。 我们 重点是合成已知或可能在体内具有 抗癌活性。 我们建议进行第一类合成， 这两种物质。 一个这样的目标是柄型大环内酯吡喃二酮 抗生素Lankacidin C，据报道具有良好的体内抗肿瘤活性 L1210白血病、6C 3 HED/OG淋巴肉瘤和B16黑色素瘤小鼠。 我们提出了一种基于分子内的对映体特异性方法， 对映体纯β-内酰胺中间体的重排反应， 在上一个资助期内，我们的实验室已经证明了这一点。 我们的第二个目标分子是C35 H47 O 9 N恶唑多烯柄型大环内酯 根霉素。 这种复杂的多功能分子在体内表现出很高的活性。 在小鼠中对L1210和P388白血病和B16黑色素瘤的活性，和 针对某些长春新碱和西帕霉素耐药的肿瘤细胞系。 最近的研究表明，根霉毒素和它的一些同类物是有效的 具有受体结合机制的微管组装抑制剂 有点类似于美登素。 我们提出的合成是 对映体特异性和高度收敛，以便提供最大的模块化 结构修饰和类似物合成的灵活性。 所提出的目标分子将作为要求严格的框架来测试 各种新的、化学选择性和立体选择性的合成 方法论。 这些方法包括使用新型官能化的和 有时是手性乙烯基锡烷亲核试剂，乙烯基锡烷的开发 β-酮基膦酸二阴离子或其作为双官能Lynch的等价物， PIN试剂，多官能内酯的对映选择性结构， 一种对映选择性的Darlene缩合和立体选择性的加工 恶唑三烯发色团。 高级中间体和新类似物 两个目标分子，唯一可通过我们的合成 方案，将被筛选的抗肿瘤活性。 结构 将进一步研究观察到的增强效力的修饰， 在这两个框架的基础上产生治疗上改进的药物。