ANALOGS OF ANTINEOPLASTIC INDOLE ALKALOIDS

抗肿瘤吲哚生物碱的类似物

• 批准号: 3299195
• 负责人: RICHARD J SUNDBERG
• 金额: $ 10.89万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3299195
• 关键词: Hodgkin's disease; alkaloids; antileukemic agent; antineoplastics; aspidosperma alkaloid; cyclic compound; drug design /synthesis /production; drug screening /evaluation; electron transport; ibogaine; indoles; microtubules; plant extracts; tubulin; vinblastine; vincristine

The purpose of this projects is to synthesize and characterize new analogs at the antineoplastic dimeric indole alkaloids of the vincristine- vinblastine type. The synthetic targets are nor and homo analogs in which methylene groups are inserted or deleted at the C-6' and C-17' position of the normal vinblastine structure. These compounds will be synthesized from a small group of iboga alkaloid intermediates prepared by synthetic methods developed in the principal investigator's laboratory. The effect of these structural changes and related substituent effects on the mechanism and efficiency of coupling will be investigated. New conditions for coupling of the iboga structures with the alkaloid vindoline will be explored with particular emphasis being placed on homolytic and electron- transfer- induced fragmentation to produce reactive intermediates for coupling. The steroelectivity of a group of open C-ring structures related to the iboga derivative cleavamine will be examined. Synthetic routes which can be adapted to utilize intermediates with a preference for either alpha or beta approach of nucleophiles will be explored. All products of coupling reactions will be characterized and identified by spectroscopic methods. The compounds will be assessed for ability to act as tubulin assembly inhibitors. Since activity as a tubulin assembly inhibitor is frequently predictive of anti-tumor activity, compounds which show such activity will be submitted to the drug development program of the National Cancer Institute for screening.

该项目的目的是合成和表征新的类似物 长春新碱的二聚吲哚生物碱- 长春碱型。 合成的靶标是nor和homo类似物，其中 亚甲基在C-6'和C-17'位置插入或缺失， 正常的长春碱结构。 这些化合物将由 一小组通过合成方法制备的伊博加生物碱中间体 是在首席研究员的实验室里研发的 这些影响 结构变化和相关取代基对机理的影响， 将研究耦合效率。 耦合的新条件 的iboga结构与生物碱文多灵将探讨与 特别强调均裂和电子转移， 诱导断裂以产生用于偶联的反应性中间体。 的 一组与iboga有关的开C环结构的立体选择性 将检查衍生物卵裂胺。 合成路线可以是 适合于利用偏好α或β的中间体 将探索亲核试剂的方法。 联轴器的所有产品 反应将通过光谱方法表征和鉴定。 将评估化合物作为微管蛋白组装体的能力 抑制剂的 由于作为微管蛋白组装抑制剂的活性通常是 作为抗肿瘤活性的预测，显示出这种活性的化合物将 提交给国家癌症研究所的药物开发计划 研究所筛选。