ANALOGS OF ANTINEOPLASTIC INDOLE ALKALOIDS

该项目的目的是合成和表征新的类似物 在长春新碱的抗肿瘤二聚体吲哚生物碱- 长春花碱型。合成的靶标是NOR和HOMO类似物，其中 亚甲基插入或删除在C-6‘和C-17’位置 正常的长春花碱结构。这些化合物将由 合成方法合成的一小部分硫磺生物碱中间体 在首席调查员的实验室里开发出来的。这些因素的影响 结构变化及相关取代基对反应机理的影响 将对耦合效率进行调查。耦合的新条件 生物碱长春花碱的iboga结构将用 特别强调均相溶解和电子转移- 诱导裂解以产生用于偶联的活性中间体。这个 一组与iboga相关的开环C环结构的立体选择性 将对衍生的裂解胺进行检测。合成路线可以是 适用于使用偏爱阿尔法或贝塔的中间体 将探索亲核分子的方法。所有联轴器的产品 反应将通过光谱方法进行表征和鉴定。 这些化合物将被评估作为微管蛋白组装的能力 抑制剂。由于作为微管蛋白组装抑制物活性经常 预测抗肿瘤活性，显示这种活性的化合物将 提交给国家癌症药物开发计划 筛查研究所。

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.