Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogs

Abstract

Four analogs, 10-methoxy (20), 12-aza (29), benz[j] (36), and 18-methoxy (38), of camptothecin [an antineoplastic drug] were obtained by total synthesis. The 2 water-soluble analogs, 10-[(carboxymethyl)oxy]- (24) and 10-[2''-(diethylamino)-ethoxy]-20(S)-camptothecin (26), with intact ring E were prepared from natural 10-hydroxycamptothecin (3). There was a good correlation between in vitro [human nasopharyngeal carcinoma] 9KB [cells] cytotoxicity and activity in the [mouse] P-388 leukemia [cells] system. The aza analog 29 was active in P-388 only at a much higher dose level than natural camptothecin (1); the 18-methoxy analog 38 exhibited activity comparable to that of 1. The water-soluble derivative 24 was inactive. The amine hydrochloride 26 showed excellent activity at a high dose level; this could be due to its hydrolysis to 3. dl-Camptothecin (17) was roughly half as active as 1, indicating that the l isomer is inactive.