新型大豆苷元苯磺酸酯的药学性质与细胞吸收利用研究

Study on pharmaceutical properties and absorption of daidzein benzene sulfonic acid ester on cells

目的:考察新型大豆苷元苯磺酸酯衍生物(D3、D4)的药学性质和细胞吸收变化,分析其构性关系。方法:利用药动团变换原理对大豆苷元(DA1)进行结构修饰,采用微波法高产率合成DA1苯磺酸酯衍生物,采用HPLC对D3、D4的药学性质进行考察,并采用软件ChemAxon16.1.18对D3、D4的部分药学性质进行计算,利用HPLC考察DA1及衍生物D3、D4在人主动脉血管平滑肌细胞(HAVSMCs)中的吸收利用率。结果:D3、D4相对DA1在乙酸乙酯中的溶解度分别提高4.73×10^5和1.09×10^5倍,表观脂水分配系数(lgP)分别为2.73±0.45和2.19±0.12,D3的水溶性相对于DA1也得以提高,D3在HAVSMCs中的吸收率达74.3%,细胞最大吸收率:D3>DA1>D4。结论:构性关系研究表明,药物的吸收利用与其理化性质密切相关,适宜的脂溶性和水溶性可使药物的细胞吸收利用得以提高。

Objective:To investigate the pharmaceutical properties and cellular absorption of novel daidzein benzene sulfonate derivatives(D3,D4),and t0 analyze their relationship between structure and properties.Methods:The two daidzein(DA1) benzene sulfonic acid ester derivatives were synthesized in high yield by microwave irradiation. The pharmaceutical properties of D3,D4 were investigated by HPLC and were calculated by the drug design software ChemAxon16.1.18. Using the experimental and calculation results,their pharmacokinetic properties were predicted. The absorption and utilization of DA1 and its derivatives were studied in human aortic vascular smooth muscle cells(HAVSMCs) by HPLC. Results:Experimental results showed that the solubility of D3,D4 were increased by 4.73×10^5 and 1.09×10^5 times relative to DA1 in ethyl acetate,and the apparent lipid water partition coefficient(lgP)were 2.73±0.45 and 2.19±0.12,respectively. The water-soluble of derivative D3 was improved relative to DA1 also. The experimental and calculation results showed that pharmaceutical properties of derivatives were fully optimized compared with DA1,indicated they had good pharmacokinetic properties and biological activity. The absorptivity of derivative D3 was 74.3% on HAVSMCs and their maximum absorptivity were D3>DA1>D4. Conclusions:The results show that the absorption and utilization of drugs are closely related to their physicochemical properties,and the absorption and utilization of the drugs on cells are optimal only with moderate liposolubility and water solubility.