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

Article abstract of 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 substitutents 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 vitro.