伏立诺他衍生物N2E的合成、鉴定及体外抗肿瘤活性研究

目的 合成伏立诺他衍生物N2E并评价其体外抗肿瘤活性. 方法 以辛二酸为原料,先在乙酸酐中回流,使分子内脱水生成辛二酸酐,然后与2-乙氧基苯胺在二氯甲烷中于0 ℃开环胺化得2-乙氧基辛二酸单酰苯胺,再经甲醇酯化和盐酸羟胺胺解得到伏立诺他衍生物N2E;采用质谱、1H NMR、13C NMR等对合成的目标物N2E进行结构鉴定.以人肺癌细胞NCI-H1299、NCI-H460、A549和胶质瘤细胞U251、MGR2为研究对象,采用MTT法考察N2E对这些肿瘤细胞株的抑制效果,同时观察N2E对人正常肝细胞LO-2的细胞毒作用. 结果 目标物经确证为伏立诺他衍生物N2E[N-(2-乙氧基苯)-N′-羟基辛二酰胺],经归一化法测得纯度约为99.1%;N2E对人肺癌细胞NCI-H1299、A549和胶质瘤细胞U251、MGR2的抑制效果强于伏立诺他(P<0.001),而对人正常肝细胞LO-2的细胞毒作用较伏立诺他弱(P<0.001). 结论 通过混合酸酐法成功合成了N2E,N2E体外对多种肿瘤细胞株呈现出显著抗增殖作用.

Study on synthesis and antitumor activity of vorinostat derivative N2E

Objective To synthesize vorinostat derivative N2E and evaluate its anti-tumor activity.Methods Suberic acid was used as raw material to produce suberoyl anhydride by dehydration in the presence of acetic anhydride,then acetic anhydride ring opening and amidation with 2-ethoxy aniline in dichloromethane at 0 ℃,and eventually N2E was produced by esterification and aminolysis.The structure of N2E was identified by MS,1H NMR and 13C NMR.The inhibitory activity of N2E against lung cancer NCI-H1299,NCI-H460,A549 cells and glioma U251,MGR2 cell lines were investigated and the cytotoxicity to LO-2 cells was observed.Results The target compound was identified as vorinostat derivative N2E [N-(2-ethoxyphenyl)-N′-hydroxyoctanediamide],and the purity was about 99.1% by normalization method.The inhibitory effect of N2E on human lung cancer cells NCI-H1299,A549 and glioma cells U251,MGR2 were stronger than that of vorinostat (P<0.001),however the cytotoxicity of N2E on human normal liver cells LO-2 was weaker than that of vorinostat (P<0.001).Conclusion N2E was successfully synthesized by mixed anhydride method,and the inhibitory effect on NCI-H1299,A549,U251 and MGR2 were significant.