A PHOTOCHEMICAL APPROACH TO CC-1065 AND ANALOGS

新型二肽CC-1065是一种有效的抗肿瘤抗生素 其已被证明比美登素更具细胞毒性， 阿霉素和放线菌素D对多种小鼠和 人类癌细胞 不幸的是，它也显示了致命的延迟 啮齿类动物中治疗性高剂量的肝毒性。 然而，Upjohn公司最近的研究表明， CC-1065高度修饰的类似物可以是相当有活性的， 具有大大降低的肝毒性。 我们建议继续目前的研究， CC-1065的合成，以及系统地合成一种 CC-1065的结构类似物的数量。 我们的多功能 光化学方法将提供各种B和C型 单位，并将提供一个新的路线，二烯酮A单位及其 类似物 此外，深入研究适当的耦合 并进行封堵程序，以便组装 三环单元。 除了CC-1065本身之外的最终目标 包括多种脱氧类似物，以及含有 硫或氧代替吲哚氮。

The novel dipeptide CC-1065 is a potent antitumor antibiotic which has been shown to be more cytotoxic than maytansine, adriamycin, and actinomycin D against a variety of murine and human cancer cells. Unfortunately, it also shows a lethal delayed hepatotoxicity at therapeutic antineoplastic doses in rodents. Recent work at the Upjohn Company has shown, however, that a highly modified analog of CC-1065 can be quite active while having a much reduced hepatotoxicity. We propose to continue our current studies aimed at completing the synthesis of CC-1065 as well as systematically synthesizing a number of structural analogs of CC-1065. Our versatile photochemical approach will provide a variety of B and C type units, and will provide a new route to the dienone A unit and its analogs. In addition, an in-depth study of appropriate coupling and blocking procedures will be made in order to assemble the tricyclic units. Final objectives in addition to CC-1065 itself include a variety of deoxy analogs, as well as analogs containing sulfur or oxygen in place of the indole nitrogens.