甘草次酸衍生物的合成及其抗肝癌活性

Synthesis and Antitumor Activities of 18α-Glycyrrhetinic Acid Derivatives

目的:以天然产物甘草次酸为原料来合成新型衍生物,并研究其体内外抗肿瘤活性。方法:利用拼合原理将具有保肝协同作用的苦参碱和氮芥类药物美法仑分别与18α-甘草次酸连接,设计合成了2个未见文献报道的新型甘草次酸衍生物7和8。目标产物经元素分析,1H-NMR,MS分析确证。采用MTT法测试甘草次酸衍生物在人肝癌细胞SMMC-7721的体外抗肿瘤活性和对大鼠正常肝细胞BRL的毒性。结果:化合物7活性较为显著且无细胞毒性,进一步进行小鼠体内试验,给药剂量为6,9μmol·kg-1,化合物7对Hep A肿瘤的抑瘤率分别为40.72%,60.12%,优于母体药物18α-甘草次酸,而给药剂量为6μmol·kg-1的美法仑的抑瘤率为39.93%。结论:化合物7体外、体内对肝癌的抗肿瘤活性均较为显著,值得进一步研究开发。

Objective： To synthesize the novel derivatives with the natural resource 18α-glycyrrhetinic acid and evaluate their antitumor activity. Method： The novel 18α-glycyrrhetinic acid derivatives （7 and 8） were synthesized by combining the matrine and nitrogen mustard melphalan with the 18α-glycyrrhetinic acid. The target compounds were characterized by 1H-NMR, MS and elemental analyses. Their antitumor activities against SMMC- 7721 cell lines and their toxicities on normal BRL cell lines were evaluated by MTT assay in vitro. Result： The compound 7 exhibited a higher antitumor activity and nontoxicity in vitro. In the in vivo test in mice, with the dose of 6, 9 μmol.kg-1, the inhibition rates of compound 7 in HepA tumor growth were 40.72% and 60. 12% , which were higher than parent drug. Meanwhile, with the dose of 6 μmol .kg-1, the inhibition rate of melphalan was 39.93%. Conclusion： The compound 7 exhibited a high antitumor activity against hepatoma cells, which is worth further studying and developing.