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以穿心莲内酯为先导物,合成了一系列结构为12-N-取代-14-脱氧穿心莲内酯的衍生物。初步评价了这些衍生物的体外抗肿瘤活性,筛选出活性显著高于穿心莲内酯的化合物4d。对于高活性化合物4d,以人肝癌HepG2细胞为体外模型,小鼠H22和S180皮下移植性肿瘤为体内模型,进一步观察其药效,发现化合物4d在体外和体内均具有显著的抗肿瘤作用。通过Annexin V/PI双染分析检测出加药后HepG2细胞的凋亡率明显增加。深入的机制研究表明,化合物4d能够使HepG2细胞中p53和Bax表达增加,同时使Bcl-2表达减少。化合物4d具有显著的体内外抗肿瘤作用,其机制可能与激活p53依赖性凋亡诱导途径有关,值得进一步研究。
A series of derivatives of 12-N-substituted-14-deoxy-andrographolide were synthesized with andrographolide as the lead. The in vitro anti-tumor activity of these derivatives was preliminary evaluated and the compound 4d with significantly higher activity than andrographolide was screened out. For the highly active compound 4d, the human hepatocellular carcinoma HepG2 cells were in vitro model, the mice H22 and S180 subcutaneous transplantation tumor model in vivo, to further observe its efficacy and found that compound 4d in vitro and in vivo have significant anti-tumor effect. The apoptosis rate of HepG2 cells was significantly increased by Annexin V / PI double staining assay. In-depth mechanism studies showed that compound 4d increased the expression of p53 and Bax in HepG2 cells and decreased the expression of Bcl-2. Compound 4d has significant antitumor activity in vitro and in vivo, and its mechanism may be related to the activation of p53-dependent apoptosis-inducing pathway, which deserves further study.