目的 以苦参碱和18α-甘草次酸作为载体对美法仑进行结构拼合,并对其体内外抗肿瘤活性进行研究。方法 以槐果碱和美法仑为原料,经过加成、酰化反应合成了美法仑衍生物2;以18α-甘草次酸和美法仑为原料,经酯化和酰化反应合成了美法仑衍生物5,目标化合物的结构经元素分析、MS、¹H-NMR确证,并采用MTT法对其进行体外抗肿瘤活性研究,对体外活性较为显著的化合物2进行小鼠体内试验。结果 目标化合物2和5的合成总收率分别为21.3%、18.1%。目标化合物2的体外抗肿瘤活性明显高于化合物5、18α-甘草次酸、苦参碱和美法仑。体内活性试验中,目标化合物2给药剂量为6、9 μmol/kg时对HepA肿瘤的抑瘤率分别为52.00%、62.12%,而6 μmol/kg美法仑的抑制率为39.93%,化合物2的抑瘤效果优于美法仑,尤以高剂量效果最为明显。结论 化合物2表现出体外、体内较高的抗肿瘤活性,值得进一步研究。

Objective To design and synthesize melphalan derivatives by combining the matrine and 18α-Glycyrrhetinic acid to melphalan, and to evaluate their antitumor activities in vitro and in vivo. Methods Sophocarpine and melphalan were used as starting materials to synthesize the melphalan derivative 2 by addition and acylation reaction; 18α-Glycyrrhetinic acid and melphalan were used as starting materials to synthesize the melphalan derivative 5 by esterification and acylation reaction. The target compounds were characterized by elemental analyses, MS and ¹H-NMR. The antitumor activities in vitro were evaluated by MTT method. Anti-tumor experiments in vivo were also done for the compound 2 displaying high activities in vitro. Results The total yield of target compound 2 and 5 were 21.3% and 18.1%. The in vitro antitumor activity experiments showed that the antitumor activity of target compound 2 was higher than those of compound 5, 18α-glycyrrhetinic acid, matrine and melphalan. The inhibition rates of tumor growth of compound 2 with 6 and 9 μmol/kg were 52.00% and 62.12%, while the inhibition rate of tumor growth of melphalan with 6 μmol/kg was 39.93%. The inhibition effect of tumor growth of compound 2 is better than that of melphalan, especially in high dose. Conclusion The compound 2 exhibits high antitumor activity in vitro and in vivo, which could be valuable for further development.

天津市卫生局科技基金资助项目(2012KZ058)