A PHOTOCHEMICAL APPROACH TO CC-1065 AND ANALOGS

点击翻译按钮获取中文摘要

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.