血根碱、白屈菜红碱衍生物的合成与体外抗HBV活性研究

目的合成季铵类苯并菲啶生物碱血根碱(1)和白屈菜红碱(2)的衍生物,评价其体外抗HBV活性,初步探讨抗HBV活性。方法以血根碱和白屈菜红碱为原料,通过结构修饰获得衍生物,采用Hep G2.2.15细胞模型评价衍生物对HBsAg和HBeAg分泌抑制活性和HBV DNA复制的抑制活性。结果血根碱和白屈菜红碱对HBsAg、HBeAg和HBV DNA复制具有较高的抑制活性,但细胞毒性较高。氧化白屈菜红碱(6)对HBV DNA的复制具有一定的抑制作用(IC50=0.75 mmol·L-1),细胞毒性较白屈菜红碱明显降低(CC50>3.0 mmol·L-1)。6-乙氧基二氢血根碱(7)和6-乙氧基二氢白屈菜红碱(8)对HBsAg和HBeAg和HBV DNA复制具有一定的抑制活性。结论季铵类苯并菲啶生物碱具有显著的体外抗HBV活性,烯胺正离子结构单元对化合物的抗HBV活性产生重要的影响。

Synthesis and in vitro anti-HBV activities of sanguinarine and chelerythrine derivatives

Objective To synthesize the derivatives of quaternary benzophenanthridine alkaloids（QBAs） sanguinarine（1） and chelerythrine（2）, and evaluate their in vitro anti-HBV activities. Methods Derivatives were synthesized with sanguinarine and chelerythrine as starting materials and their anti-HBV activities were evaluated, namely, inhibiting the secretion of hepatitis B surface antigen（HBsAg）, hepatitis B e antigen（HBeAg）, and HBV DNA replication on Hep G 2.2.15 cells. Results Sanguinarine and chelerythrine significantly inhibited HBsAg and HBeAg secretion and HBV DNA replication on Hep G 2.2.15 cells, but these 2 compounds possessed high cytotoxicity. Oxychelerythrine（6） showed moderate activity（IC50=0.75 mmol·L-1） on HBV DNA replication with decreased cytotoxicity（CC503.0 mmol·L-1）; 6-ethyldihrdrosanguinarine（7） and 6-ethyldihydrochelerythrine（8） moderately inhibited HBsAg, HBeAg secretion and HBV DNA replication. Conclusion The quaternary imine cation in QBAs plays an important role in their anti-HBV activity and cytotoxicity.