Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogs. Structure-activity correlations

• Published in: Journal of medicinal chemistry 1987-10, Vol.30 (10), p.1774-1779
• Main Authors: Wani, Mansukh C, Nicholas, Allan W, Manikumar, Govindarajan, Wall, Monroe E
• Format: Article
• Language: English
• Subjects: Animals; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Cell Line; Leukemia L1210 - drug therapy; Plant Extracts - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00393a016

Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.