水飞蓟宾丹酚酸衍生物的制备及成药性研究

Preparation and pharmaceutical properties research of silybin phenolate derivatives

关键词:  水飞蓟宾  迷迭香酸  丹参素  缩合反应  成药性评价  慢性肝炎  肝纤维化

Key words:  silybin  rosmarinic acid  danshensu  condensation reaction  drug evaluation  chronic hepatitis  hepatic fibrosis

摘要:

[目的] 使水飞蓟宾（SLB）通过酯化缩合反应对其进行分子结构改造，生成丹酚酸酯衍生物，并对其成药性进行初步研究。[方法] 将水飞蓟宾分别与丹参活性成分迷迭香酸（RA）和丹参素（DSS），采用酯化缩合反应依次得到水飞蓟宾迷迭香酸酯（RA-SLB）和水飞蓟宾丹参素酯（DSS-SLB），通过氢谱、碳谱和质谱确证了丹酚酸酯衍生物的结构，比较了丹酚酸酯衍生物与水飞蓟宾溶解度差异，并对其进行抗肝损伤作用研究、脂肪肝的保护作用等的成药性评价。[结果] 与水飞蓟宾相比，丹酚酸酯衍生物溶解度显著提高，并且在水中的稳定性良好。与刀兰球蛋白引起急性免疫性肝损伤模型组相比，RA-SLB的低剂量组对血清丙氨酸氨基转移酶（ALT）、门冬氨酸氨基转移酶（AST）和乳酸脱氢酶（LDH）含量升高均有显著降低作用，差异具有统计学意义（P<0.05），DSS-SLB组对刀兰球蛋白引起的肝损伤在实验中有改善肝功能的趋势，但与模型组比较无统计学差异（P>0.05）。与DL-乙硫氨酸诱导脂肪肝模型组相比，RA-SLB组能显著降低肝组织中的三酰甘油（TG）含量（P<0.05），其他各给药组对TG含量的升高无显著影响，差异无统计学意义（P>0.05）。[结论] RA-SLB具有显著的保护肝损伤及改善脂肪肝活性作用，具有很好的成药前景。

Abstract:

[Objective] The molecular structure of silybin was modified by esterification and condensation reaction to produce salvianolic acid ester derivatives，and its drug property were preliminarily studied. [Methods] The silybin rosemary ester（RA-SLB） and silybin danshensu ester（DSS-SLB） were obtained by esterification Condensation reaction of silybin（SLB） with the active components of salvia miltiorrhiza（RA） and danshensu（DSS），respectively. The structure of salvianolic acid ester derivatives was confirmed by hydrogen spectrum，carbon spectrum and mass spectrum，and the solubility differences between salvianolic acid ester derivatives and silybin were compared，and their anti-liver injury effects and the evaluation of the protective effect of fatty liver were studied. [Results] Compared with silybin，the solubility of salvianolic acid ester derivatives is significantly improved，and the stability in water is good. Compared with the model group of acute immune liver injury caused by scalan globulin，the low-dose group of RA-SLB significantly reduced the content of serum alanine aminotransferase（ALT），aspartate aminotransferase（AST） and lactate dehydrogenase（LDH）（P<0.05）. The DSS-SLB group had a tendency to improve liver function in the experimental scheme of liver injury caused by scalan globulin，but there was no statistical difference compared with the model group（P>0.05）. Compared with DL-ethionine induced fatty liver model group，RA-SLB group can significantly reduce the content of triglyceride（TG） in liver tissue（P<0.05），while other administration groups have no significant effect on the increase of TG content（P>0.05）. [Conclusion] RA-SLB has a significant effect on protecting liver injury and improving the activity of fatty liver，and has a good prospect of patent medicine.