新型14β-侧链紫杉醇衍生物的合成及构效关系研究  

SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIPS OF NOVEL 14β SIDE CHAIN TAXOL DERIVATIVES

作　　者：刘瑞武[1] 尹大力[1] 王东辉[1] 李春[1] 郭积玉[1] 梁晓天[1] 

机构地区：[1]中国医学科学院中国协和医科大学药物研究所

出　　处：《药学学报》1998年第12期910-918,共9页Acta Pharmaceutica Sinica

摘　　要：以生物合成得到的紫杉烷ｓｉｎｅｎｘａｎＡ为起始原料，合成一系列新的紫杉醇衍生物，以寻找高效低毒、抗瘤谱广、综合性能好的新一代紫杉醇类抗癌药，并进行构效关系研究。从半合成的紫杉烷中间体７出发，分别经５步和６步反应成功地合成了４位羟基和４位乙酸酯两类共８个新的１４β侧链紫杉醇衍生物，２位基团为苯甲酸酯、间氯苯甲酸酯、正戊酸酯和苯乙酸酯。将目标化合物连同已合成的２个１４β侧链紫杉醇衍生物进行了微管聚合试验和体外肿瘤细胞抑制试验。所有化合物在浓度为１０μｍｏｌ·Ｌ－１时对微管无作用。在体外肿瘤细胞抑制试验中，大部分化合物显示边缘细胞毒活性。１４β侧链紫杉醇衍生物的构效关系与１３α侧链紫杉醇衍生物有所不同，２位脂肪酸酯与２位芳香酸酯活性相当，表明２位基团的改变对活性无明显影响。４位羟基衍生物的活性好于４位乙酸酯。In order to develop new generation of taxol like anticancer agents with fewer side effects, improved activity, superior pharmacological properties and broad antitumor spectrum, along with structure activity relationship study, a series of new taxol derivatives are to be synthesized starting from sinenxan A a biosynthetic taxane. Eight new 14β side chain taxol derivatives with 4 OH and 4 Ac were synthesized in 5 and 6 steps from semisynthetic taxoid intermediate 7, respectively. These included taxol derivatives modified at C 2 position with benzoate, m Cl benzoate, valerate and phenylacetate. All target compounds together with two other 14β side chain taxol derivatives were tested in a microtubule assembly assay, and in an in vitro cytotoxicity assay (KB, A2780, HCT 8 cell line). All compounds had no effect in the microtubule assembly assay at 10 μmol·L -1 . Most of them showed marginal activity in the in vitro cytotoxicity. The structure activity relationship was different from taxol derivatives. 2 Aliphatic ester displayed similar activity to 2 aromatic ester, which indicated that the aromatic group at C 2 position was not important for cytotoxicity. Comparing among themselves, 4 OH deravitives possessed stronger activity than 4 Ac.

关 键 词：新型 侧链紫杉醇 紫杉醇 衍生物 构效关系 合成 

分 类 号：TQ464.9[化学工程—制药化工] R931.71[医药卫生—生药学]