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Four analogues, 10-methoxy (20), 12-aza (29), benz[j] (36), and 18-methoxy (38), of camptothecin were obtained by total synthesis. The two water-soluble analogues, 10-[(carboxymethyl)oxy]- (24) and 10-[2'-(diethylamino)-ethoxy]-20(S)-camptothecin (26), with intact ring E were prepared from natural 10 hydroxycamptothecin (3). In general, there was a good correlation between in vitro 9KB cytotoxicity and activity in the P-388 leukemia system. While the aza analogue 29 was active in P-388 only at a much higher dose level than natural camptothecin (1), the 18-methoxy analogue 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.

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