摘要
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、^(13)C 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。
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 dichloromethaue 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 cytotoxieity 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 eytotoxicity 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.
出处
《广东药科大学学报》
CAS
2017年第2期187-190,共4页
Journal of Guangdong Pharmaceutical University
基金
广东省科技计划项目(2013B021800079)
