N-苄基吲哚类熊果酸衍生物的合成及抗肝癌活性

为开发高效低毒的抗肝癌天然产物衍生物,依据药物拼合原理设计并合成了一系列未见文献报道的熊果酸衍生物。将熊果酸与不同取代的N-苄基吲哚片段通过Claisen-Schmidt缩合反应得到目标化合物,其化学结构均经过核磁氢谱、核磁碳谱以及质谱的联合确证。采用噻唑蓝(MTT)法考察其体外抗肝癌活性,结果表明,2-{1-(2-氟苄基)-1 H-吲哚基]-3-次甲基}-3-羰基熊果酸(4b)与2-{1-(3-氟苄基)-1 H-吲哚基]-3-次甲基}-3-羰基熊果酸(4c)对HepG2及BEL-7402两种肝癌细胞株的抑制活性优于熊果酸及阳性对照药氟尿嘧啶,同时对正常肝细胞L02的毒性显著降低。化合物4c的体外抗肝癌活性最为理想(针对HepG2的IC₅₀值为3.22μmol/L,选择性指数为6.89),分子对接实验模拟其作用靶标或为RNA聚合酶Ⅱ,可对其深入研究用以开发高效低毒的抗肝癌药物。

Synthesis and Anti-hepatocellular Carcinoma in Vitro of Ursolic Acid Derivatives Bearing N-benzylindole Moieties

To develop natural derivatives with high efficiency and low toxicity for anti-hepatoma,a series of novel ursolic acid derivatives were designed and synthesized via the principle of pharmacochemical molecular combination.The target compounds were obtained by Claisen-Schmidt condensation reaction between ursolic acid and different substituted N-benzylindole,then characterized via 1HNMR,13 CNMR,and mass spectrometry,and investigated for anti-hepatocellular activity by MTT method.(1 S,2R,4aS,6aS,6bR,12aR,E)-11-((1-(2-Fluorobenzyl)-1 H-indol-3-yl)methylene)-1,2,6 a,6b,9,9,12 a-heptamethyl-10-oxo-1,3,4,5,6,6 a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-4 a(2H)-carboxylic acid(4b)and(1 S,2R,4aS,6aS,6bR,12aR,E)-11-((1-(3-fluorobenzyl)-1 H-indol-3-yl)methylene)-1,2,6 a,6b,9,9,12a-heptamethyl-10-oxo-1,3,4,5,6,6 a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-4 a(2H)-carboxylic acid(4c)showed higher antiproliferative activity against the HepG2 and BEL-7402 cell lines in comparison with the positive-control drug 5-fluorouracil and ursolic acid,and exhibited significantly lowered cytotoxic activities against human normal liver cells(L02).Compound 4c exhibited the most potent antiproliferative activity and commendable selectivity between cancer and normal cells(IC₅₀=3.22μmol/L against the HepG2 cells,Selectivity index=6.89).The results of a docking study that involved placing compound 4c into the RNA polymeraseⅡbinding site revealed that its mode of action was possibly as a RNA polymeraseⅡinhibitor.In conclusion,compound 4c may be a valuable candidate for further studies aiming at the development of effective and harmless anti-hepatoma drugs.