A PHOTOCHEMICAL APPROACH TO CC-1065 AND ANALOGS

CC-1065是一种重要的抗肿瘤抗生素。 甚至比放线菌素、长春花碱或 Maytansine，并已被NCI(NSC298223)选择用于临床前 毒理学研究。不同寻常的三吲哚二肽结构以及 烷基化基团的存在似乎是造成这种情况的原因 生物活性。因此，开发一个好的综合方法是很重要的 这不仅将导致CC-1065，而且还将允许快速合成 许多潜在的活性类似物。 我们提出了一种非常有效和新颖的方法来合成 这个重要的分子。我们将构建个体 二氢吡咯并[3，2-e]吲哚单元的新型光化学法(6PI电子) 易制备的前体的环化反应。我们最近确认了 这种方法的可行性通过成功地实施这样一个 二吡咯乙烯模型体系的环化反应。 我们的合成方案的收敛性质将使我们能够迅速 构造许多CC-1065的类似物，其中OME基团被替换为 CH_3、C_1或H，甚至O和S取代环中的N。来自DNA CC-1065的结合研究和我们期待的分子模型检验 这些类似物也显示出抗肿瘤活性。

The dipeptide CC-1065 is an important antitumor antibiotic which exhibits significantly higher cytotoxicity than even actinomycin, vinblastine, or maytansine, and has been selected by the NCI (NSC298223) for preclinical toxicology studies. The unusual triindole dipeptide structure as well as the presence of an alkylating group appear to be responsible for this bio-activity. It is thus important to develop a good synthetic approach which would lead not only to CC-1065 but also allow a rapid synthesis of numerous, potentially active analogs. We propose an extremely efficient, and novel approach to the synthesis of this important molecule. We shall construct the individual dihydropyrrolo[3,2-e] indole units by a novel photochemical (6 Pi electron) cyclization of easily prepared precursors. We have recently confirmed the feasibility of this approach by successfully carrying out such a cyclization of a dipyrrylethylene model system. The convergent nature of our synthetic scheme will allow us to rapidly construct many analogs of CC-1065, where the OMe groups are replaced by CH3, C1 or H, and even where O and S replace the N in the rings. From DNA binding studies on CC-1065 and examination of molecular models we expect these analogs to also show antitumor activity.