新型7-乙基-10-羟基喜树碱衍生物的合成及其体外抗肿瘤活性

Synthesis and In vitro Anti-tumor Activities of A Novel 7-Ethyl-10-hydroxy Camptothecin Derivative

以乙二醇为起始原料,依次经亲核取代和点击反应合成了一种7-乙基-10-羟基喜树碱(SN38)的新型葡萄糖残基衍生物(FSY02),其结构经~1H NMR,^(13)C NMR和HR-MS(ESI)表征。采用四甲基偶氮唑盐比色法(MTT法)研究了FSY02对人非小细胞肺癌细胞(A549)、人肝癌细胞(HepG2)、人结直肠癌细胞(SW-480)、人宫颈癌细胞(Hela)和人乳腺癌细胞(MDA-MB-231)的生长抑制作用。并采用Hoechst 33258染色和Western blot技术对给药后的结肠癌细胞凋亡情况和相关凋亡信号通路Caspase 3、 Bax和Bcl-2蛋白的表达情况进行了检测。结果表明:FSY02具有广谱抗癌活性,IC_(50)=0.118～4.295μmol·L^(-1),优于对照组伊立替康(IC_(50)=14.330～65.353μmol·L^(-1))。Hoechst 33258染色及Western blot检测结果显示:FSY02通过上调Caspase 3和Bax的表达,下调凋亡抑制蛋白Bcl-2的表达诱导细胞凋亡。

A novel glucose residue derivative(FSY02) of 7-ethyl-10-hydroxy camptothecin(SN38) was synthesized from glycol by nucleophilic substitution and click reaction. The structure was characterized by 1 H NMR, 13 C NMR and HR-MS(ESI). MTT assay was used to estimate the anti-tumor effect of FSY02 on A549, HepG2, HCT-116, Hela, MDA-MB-231 cell lines. Hoechst 33258 staining was used to measure the apoptosis of colon cancer cells after administration. Furthermore, downstream apoptosis-related targets of Caspase-3, Bax, Bcl-2 in colon cancer cell was investigated by Western blot. The results showed that FSY02 has broad spectrum anticancer activity with IC 50 of 0.118~4.295 μmol·L^-1 , better than the control group Irinotecan( IC 50 =14.330~65.353 μmol·L^-1 ). The results of Hoechst 33258 staining and Western blot showed that FSY02 could up-regulate the expression of Caspase-3 and Bax, and down-regulate the expression of Bcl-2 protein to induce apoptosis.