【摘要】 目的以甘草次酸（GA）为母核进行结构修饰,寻找高效低毒的抗肿瘤先导化合物。方法在前期研究的基础上,基于拼合原理,在GA C-30位引入苄基,并在C-3位分别通过酯键与酰胺键引入组氨酸结构片段;通过¹H-NMR、¹³C-NMR和HRMS对衍生物结构进行确认;采用四甲基偶氮唑蓝（MTT）法评价其对人肝癌细胞HepG2、人肺癌细胞A549和人结肠癌细胞HCT-116的细胞毒活性,同时采用人正常肝细胞L02和大鼠心肌细胞H9C2评价其毒性;进一步采用4′,6-二脒基-2-苯基吲哚（DAPI）染色法观察优势化合物对细胞核形态的影响。结果本研究共得到6个结构新颖的GA抗肿瘤衍生物。细胞活性评价表明这些衍生物均表现出一定的抗肿瘤活性,其中化合物6抗肿瘤活性最强,其对HepG2细胞的抗肿瘤活性[半数抑制浓度(IC₅₀)=2.98±0.69μmol·L^-1]强于阳性药索拉菲尼(IC₅₀ =7.07±0.30μmol·L^-1),而对人正常肝细胞L02的毒性(IC₅₀ =4.93±0.03μmol·L^-1)弱于索拉菲尼(IC₅₀ =1.97±0.65μmol·L^-1),表现出一定的细胞毒选择性;DAPI染色研究进一步表明化合物6可通过诱导HepG2细胞核碎裂使细胞凋亡。结论本研究在GA母核中引入苄基与氨基酸片段后得到高效低毒的抗肿瘤衍生物,为GA类抗肿瘤先导化合物的发现奠定基础。更多还原

【Abstract】 Objective To search for the lead compounds with high anti-tumor activity and low toxicity by structural modification of glycyrrhetinic acid（GA）.Methods Based on the team′s previous research, according to the combination principle, benzyl group was introduced into C-30 position of GA,and histidine structure fragment was introduced into C-3 position by ester bond and amide bond, respectively.The structures were confirmed by ¹H-NMR,¹³C-NMR and HRMS.The activity of the compounds on human hepatoma cell HepG2,human lung cancer cell A549 and human colon cancer cell HCT-116 and the toxicity on human normal liver cell L02 and rat cardiomyocyte H9 C2 were evaluated by MTT method; 4′,6-diamidine-2-phenyl indole（DAPI） staining was used to observe the effect of dominant compounds on nuclear morphology.Results In this study, 6 novel anti-tumor derivatives of GA were obtained.The evaluation of cell activity showed that these derivatives showed certain anti-tumor activity, and compound 6 showed the strongest activity.The compound 6 showed stronger antitumor activity against HepG2 cells(IC₅₀=2.98±0.69 μmol·L^-1) than the positive drug sorafenib(IC₅₀=7.07±0.30 μmol·L^-1).However, it exhibited lower toxicity against human normal hepatocytes L02 cells(IC₅₀=4.93±0.03 μmol·L^-1) than sorafenib(IC₅₀ =1.97±0.65 μmol·L^-1),showing certain cytotoxic selectivity.DAPI staining further showed that compound 6 could produce cytotoxicity by inducing nuclear fragmentation of HepG2.Conclusion In this study, high efficiency and low toxicity antitumor derivatives were obtained by introducing benzyl group and amino acid fragments into the parent nucleus of GA,providing reference for the discovery and research of GA antitumor lead compounds.更多还原