Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations.
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.
Wani
M C
MC
Research Triangle Institute, Research Triangle Park, North Carolina 27709.
Nicholas
A W
AW
Manikumar
G
G
Wall
M E
ME
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line; D007939:Leukemia L1210 / Q000188:drug therapy*; D010936:Plant Extracts / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D010936:Plant Extracts; D002166:Camptothecin