胆酸偶联喜树碱衍生物E2、G2的稳定性研究

目的考察胆酸偶联喜树碱衍生物20(S)-O-甘氨酸-脱氧胆酸喜树碱(E2)、20(S)-O-醋酸-脱氧胆酸喜树碱(G2)在大鼠血浆和人工胃肠液中的稳定性。方法建立并优化高效液相色谱法,测定并比较E2、G2和喜树碱在大鼠血浆和人工胃肠液中的稳定性。结果在血浆和人工胃肠液中三者均有不同程度的减少,但E2、G2减少量均低于喜树碱。相对于人工胃肠液,三者在大鼠血浆中减少最为明显。三者在3种生物基质中发生了相似的降解,E2、G2主要发生水解生成喜树碱,而喜树碱则主要发生了内酯环开环。结论通过偶联胆酸合成得到的喜树碱衍生物在生物基质中具有明显高于喜树碱的稳定性,有助于维持喜树碱药效团内酯环的稳定。

Stability of camptothecin analogues conjugated with bile E2 and G2

Objective To investigate the stability of the two novel camptothecin analogues conjugated with bile acid, 20(S)-O-glycine-deoxycholate camptothecin (E2) and 20(S)-O-acetate-deoxycholate camptothecin (G2), in the rat plasma, simulated gastric fluid, and simulated intestinal fluid. Methods HPLC-UV methods were optimized, and the changes of the content of the compound in biological matrix were detected. Results The contents of E2, G2 and camptothecin in the three biological matrixs were decreased with varying degrees, but decrements of E2 and G2 were lower than those of camptothecin. Compared to those in simulated gastric fluid and simulated intestinal fluid, the reductions were most obvious in rat plasma. The related chromatograms revealed a similar degradation of E2, G2, and camptothecin, through which the lactone in camptothecin were hydrolyzed, and E2 and G2 were hydrolyzed to produce camptothecin with a lactone. Conclusion The synthesis of camptothecin derivatives obtained by coupling cholic acid would significantly improve the stability of camptothecin in the biological matrixs, and remains a E-ring form of camptothecin, which keeps the antitumor activity.