Wani M C, Ronman P E, Lindley J T, Wall M E
J Med Chem. 1980 May;23(5):554-60. doi: 10.1021/jm00179a016.
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.
通过全合成获得了喜树碱的四种类似物，即10-甲氧基（20）、12-氮杂（29）、苯并[j]（36）和18-甲氧基（38）。由天然的10-羟基喜树碱（3）制备了两种具有完整E环的水溶性类似物，即10-[(羧甲基)氧基]-（24）和10-[2'-(二乙氨基)-乙氧基]-20(S)-喜树碱（26）。一般来说，体外9KB细胞毒性与P-388白血病系统中的活性之间存在良好的相关性。虽然氮杂类似物29在P-388中仅在比天然喜树碱（1）高得多的剂量水平下才有活性，但18-甲氧基类似物38表现出与1相当的活性。水溶性衍生物24无活性。胺盐酸盐26在高剂量水平下表现出优异的活性。这可能是由于其水解为3。消旋喜树碱（17）的活性约为1的一半，表明l异构体无活性。
