目的:合成具有不同电负性基团的熊果酸衍生物并研究其抗癌活性.方法:合成一系列携带正电性基团或负电性基团的熊果酸衍生物,并用软件预测衍生物油水分配系数及水溶性的改善情况；采用MTT法考察熊果酸衍生物对人前列腺癌PC-3细胞的抑制活性；采用细胞周期分析及AnnexinV/PI双标记法探讨其抗癌机制.结果:熊果酸衍生物的水溶性较熊果酸有明显改善；荷负电基团的熊果酸衍生物抑癌活性远低于熊果酸,而负载正电性基团显著提高了熊果酸的体外抗癌活性,其作用机制为诱导细胞发生凋亡及细胞周期阻滞；其中熊果酸衍生物UA-3,UA-4,UA-5b的水溶性提高70倍以上,对PC-3细胞的IC50(48h)均＜10 μmol·L-1,将细胞阻滞于G0/G1期并具有诱导凋亡作用(凋亡率均＞50％).结论:采用正电性基团修饰熊果酸是提高抗癌效果并改善其水溶性的有效途径之一.%Objective: To design and synthesize a series of novel ursolic acid (UA) derivatives bearing different kinds of charge and to study their in vitro anti-tumor activities. Methods: Ursolic acid derivatives bearing different charges were prepared and their water-solubility as well as logP values were predicted. Their cytotoxicity a-gainst PC-3 cells was evaluated by MTT assay. Cell cycle analysis and Annexin V/PI dual staining were performed to investigate the anticancer mechanism. Results: The water-solubility of UA was enhanced via the chemical modification. The derivatives bearing negative charge had weaker cytotoxic effects than UA upon PC-3 cells. However, the ones bearing positive charge exhibited more powerful cytotoxicity than UA against the same cell line, involving the occurrence of apoptosis as well as cell cycle arrest. In particular, both elevated water-solubility ( >70-fold of that of UA) and a IC50(48 h) less than 10 μmol·L-1 against PC-3 cells were achieved by three UA derivatives; UA-3 , UA-4 and UA-5b. The cell-cycle arrest in G0/G1 as well as apoptosis ( > 50% ) was observed after the treatment of one of the three derivatives against PC-3 cells. Conclusion: The introduction of groups of positive charge to UA is an effective way to improve its water-solubility and anti-proliferative activities.
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