目的 以苦參堿和18α-甘草次酸作為載體對(duì)美法侖進(jìn)行結(jié)構(gòu)拼合,并對(duì)其體內(nèi)外抗腫瘤活性進(jìn)行研究。方法 以槐果堿和美法侖為原料,經(jīng)過加成、?；磻?yīng)合成了美法侖衍生物2;以18α-甘草次酸和美法侖為原料,經(jīng)酯化和?；磻?yīng)合成了美法侖衍生物5,目標(biāo)化合物的結(jié)構(gòu)經(jīng)元素分析、MS、¹H-NMR確證,并采用MTT法對(duì)其進(jìn)行體外抗腫瘤活性研究,對(duì)體外活性較為顯著的化合物2進(jìn)行小鼠體內(nèi)試驗(yàn)。結(jié)果 目標(biāo)化合物2和5的合成總收率分別為21.3%、18.1%。目標(biāo)化合物2的體外抗腫瘤活性明顯高于化合物5、18α-甘草次酸、苦參堿和美法侖。體內(nèi)活性試驗(yàn)中,目標(biāo)化合物2給藥劑量為6、9 μmol/kg時(shí)對(duì)HepA腫瘤的抑瘤率分別為52.00%、62.12%,而6 μmol/kg美法侖的抑制率為39.93%,化合物2的抑瘤效果優(yōu)于美法侖,尤以高劑量效果最為明顯。結(jié)論 化合物2表現(xiàn)出體外、體內(nèi)較高的抗腫瘤活性,值得進(jìn)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.

天津市衛(wèi)生局科技基金資助項(xiàng)目(2012KZ058)