甲基对苯醌的理化性质及类药性预测研究

Physicochemical Properties of Methyl-p-Benzoquinone and Prediction of Its Drug Likeness

目的:测定甲基对苯醌的平衡溶解度以及油水分配系数,并分析其对不同肿瘤细胞的细胞毒活性。方法:采用摇瓶法-HPLC法测定甲基对苯醌在不同pH溶液中的平衡溶解度和油水分配系数。色谱条件:采用Ecosil-C18色谱柱(4.6 mm×250 mm,5μm),流动相为乙腈-0.1%甲酸水溶液(70:30),流速1.0 mL/min,检测波长250 nm,柱温30℃,进样量10μL。利用SwissADME和pkCSM预测药物的类药性,采用MTT法分析甲基对苯醌对HT29、CT26、Caco-2、Hela、HepG25株细胞的细胞毒活性。结果:甲基对苯醌在pH为1.2、2.0、5.0、6.7、7.0、7.4的溶液中,12 h的平衡溶解度分别为7.65、8.05、9.31、8.43、9.33、7.93 mg/mL,油水分配系数分别为0.78、0.80、0.83、0.82、0.77、0.82,SwissADME预测的溶解度和油水分配系数均与实验结果一致。同时预测结果发现,甲基对苯醌具有较好的类药性以及较弱的血脑屏障透过性。甲基对苯醌对5株细胞的IC50依次为7.98、3.21、8.96、7.96、6.31μmol/L。结论:测定甲基对苯醌平衡溶解度和油水分配系数的摇瓶法-HPLC法简单可行,且在pH 5.0~7.0的溶液条件下能够适当增强甲基对苯醌的溶解度,同时药物的ADME/T在线预测软件具有一定的可靠性,甲基对苯醌对HT29、CT26等多株细胞具有显著的抑制作用。

Objective:To determine the equilibrium solubility and oil-water partition coefficient of methyl-p-benzoquinone,and analyze the cytotoxic activity against different tumor cells.Methods:The equilibrium solubility and oil-water partition coefficient of methyl-p-benzoquinone in different pH solutions were determined by shake flask-HPLC method.Chromatographic conditions:Ecosil-C18 chromatographic column(4.6 mm×250 mm,5µm),the mobile phase was acetonitrile-0.1%formic acid aqueous solution(70:30),the flow rate was 1.0 mL/min,the detection wavelength was 250 nm,the column temperature was 30℃,and the injection amount was 10µL.SwissADME and pkCSM were used to predict the drug likeness.The cytotoxic activity of methyl-p-benzoquinone against HT29,CT26,Caco-2,Hela and HepG2 cells was analyzed by MTT method.Results:The equilibrium solubility of methyl-p-benquinone in solutions with pH of 1.2,2.0,5.0,6.7,7.0 and 7.4 for 12 h was 7.65,8.05,9.31,8.43,9.33 and 7.93 mg/mL,respectively,and the oil-water partition coefficients were 0.78,0.80,0.83,0.82,0.77,0.82,respectively.The solubility and oil-water partition coefficient predicted by SwissADME were consistent with the experimental results.At the same time,the prediction results showed that methyl-p-benzoquinone had better drug likeness and weaker blood-brain barrier permeability.The IC50 of methyl-p-benzoquinone against 5 cell lines were 7.98,3.21,8.96,7.96,6.31µmol/L,respectively.Conclusion:HPLC method is simple and feasible.Moreover,the solubility of methyl-p-benzoquinone can be properly enhanced under the condition of pH 5.0~7.0 solution.At the same time,the ADME/T online prediction software for drugs has certain reliability.Methyl p-benzoquinone has significant inhibitory effect on multiple cell lines such as HT29 and CT26.