4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素的合成和抗肿瘤活性

SYNTHESIS AND ANTITUMOR ACTIVITY OF 4-ALKYLTHIO-4-DEOXY-4’-DEMETHYLEPIPODOPHYLLOTXIN DERIVATIVES

摘要: 对4’-去甲表鬼臼毒素的C₄位进行化学修饰,合成和筛选了10个4-烷硫基-4-脱氧-4’-去甲表鬼臼毒素衍生物以进一步研究C₄位不同的原子和取代基与活性之间的关系及寻找结构简单、活性更强的抗肿瘤新药。4’-去甲表鬼臼毒素与硫醇在三氟化硼·乙醚或三氟乙酸存在下生成相应的硫醚,也可用硫醇与4β-溴-4-脱氧-4’-去甲表鬼臼毒素反应生成相应的硫醚。在体外筛选中,化合物10和12抑制L1210白血病细胞的活性与依托泊甙相当或更强,化合物9,10,12和15抑制KB细胞的活性与依托泊甙相当或更强。

Abstract: As a continuing part of our study on the chemistry and antitumor activity of podo-phyllotoxin , 11 new C-4 S-substituted poclophyllotoxin derivatives were synthesised and screened invitro against L1210 leukemia and KB cells. Thus, 4′-demethylepipodophyllotoxin was reacted withthiols in the presence of BF₃.Et₂O or trifluroacetic acid to give thioethers. In addition, 4-bromo-4-de-oxy-4′-demethylepipodophyllotoxin, when reacted with thiols, also gave rise to correponding thioether(4-alkylthio-4-deoxy-4′-demethylepipodophyllotoxins). Compounds 10 and 12 have the same activityas etoposide in the inhibition against L1210 leukemia, and compounds g, 10, 12 and 15 also havecomparable activity with etoposide against KB cells.