鬼臼毒素类的化学与抗肿瘤活性研究——Ⅸ.4-(芳甲亚胺基)及4-烷胺基-4-脱氧-4′-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

STUDIES ON THE CHEMISTRY AND ANTITUMOR ACTIVITIES OF PODOPHYLLOTOXINS Ⅸ. SYNTIIESIS AND ANTITUMOR ACTIVITIES OF 4-(ARYLMETHINEIMINO) OR 4-(ALKYLAM1NO)-4-DEOXY-4-DEMETHYLEPIPODOPHYLLOTOXIN ANALOGUES

本文为鬼臼毒素的化学和抗肿瘤活性研究的一部分,设计合成和筛选了4-(芳甲亚胺基)(Ⅰ)及4-烷胺基-4-脱氧-4′-去甲表鬼臼毒素衍生物(Ⅱ)22个。(Ⅰ)对KB细胞的抑制活性普遍较依托泊甙(VP-16)强。(Ⅱ)中(Ⅱ_1)及(Ⅱ_8)对L_(1210)的抑制活性与依托泊甙相当,但对KB细胞活性较依托泊甙弱。

4-Amino-4-deoxy-4'-demethylepipodophyllotoxin was prepared stereoselectively by the reaction of 4'-demethylepipodophyllotoxin with HN_3 in the presence of BF_3. Et_2O, followed by catalytic hydrogenation. Thus, twenty two 4- (arylmethineimino)or 4- (alkylamino)-4-deoxy-4'-demethylepipodophyllotoxin analogues were synthesized by condensation of 4-amino-4-deoxy-4'-demethylepipodophyllotoxin with corresponding aromatic or aliphatic aldehydes or ketones under refluxing or in the presence of NaBH_3CN. The antitumor activities of most of the compounds Ⅰ_(1～8) were superior to that of etoposide against KB cells in vitro test. The compounds Ⅱ_(1～14) showed remarkable activity against L_(1210) cells.