10位结构修饰14β-侧链紫杉醇衍生物的合成及其抗肿瘤活性

Synthesis and Their Antitumor Activities of C_(10) Modified Taxol Derivatives with 14β-Side Chain

为了寻找高效低毒、抗瘤谱广、综合性能好又不依赖自然资源的新一代紫杉醇类抗癌药 ,以组织培养得到的紫杉烷sinenxanA为最初起始原料 ,以紫杉烷中间体 (3)和 (16 )为合成原料合成了 10位为羰基、羟基、甲氧基乙酸酯、苄氧基乙酸酯、羟乙酸酯等共 6个新的 14β 侧链紫杉醇衍生物 .并对目标化合物进行了抗肿瘤体外试验和微管蛋白聚合试验 .结果表明所有化合物对KB细胞的IC50 >10 μg ,在浓度为 10～ 5 μmol/L时对微管蛋白无聚合作用 .说明分子的 10位结构修饰对活性无明显影响 .

In order to develop a new generation of taxol like anticancer agents with fewer side effects,improved activity,superior pharmacological properties and broad antitumor specffum,six new C 10 modified Taxol derivatives with a 14β side chain,including C 10 oxo,hydroxy,methoxyacetate,benzyloxyacetate and hydroxyacetate,were synthesized from taxane intermediates (3) and (16) respectively,which were derived from sinenxan A,a biosynthetic taxane.All the target compounds were tested in a tubulin assembly assay.and in an in vitro cytotoxicity assay (KB cell line).Compared with taxol,they showed significantly decreased activity in the cytotoxicity assay in vitro against KB.In the tubulin assembly assay they did not show any activity at 10 μmol/L.This demonstrated that the modification at C 10 position did not have obvious effects on anticancer activity and was similar to the structure activity relationship of the Taxol SAR.