苄基葡萄糖硫苷的设计合成及心肌保护活性研究

Design and synthesis of benzyl thioglucosides and their protective effects on myocardial cells

目的设计合成具有心肌保护作用的葡萄糖硫苷化合物。方法以四乙酰基-α-溴代葡萄糖为原料合成四乙酰基-β-硫代葡萄糖,再与取代溴苄反应制得葡萄糖硫苷,最后脱去乙酰基得到目标化合物。通过体外心肌细胞的缺氧/复氧损伤模型评价其心肌保护活性。结果与结论合成了14个苄基葡萄糖硫苷新化合物。初步药理评价表明,该类化合物对缺氧/复氧损伤心肌具有一定的保护作用,其中3个化合物的活性强于红景天苷,并呈剂量依赖关系。

In our earlier studies,we found that benzyl thioglucoside S01（3＇,4＇,5＇-trimethoxybenzyl-β-thioglucoside） could protect SH-SY5Y cells from the damage induced by glutamate and oxygen-glucose deprivation.These findings encouraged us to study its mechanism of action.Then we revealed that S01＇s activity was mainly related to following actions：decreasing the intracellular production of ROS;inhibiting the decrease in SOD activity;scavenging free radicals.The findings indicated that analogues of S01 may also have protective effects on myocardial cells against ischemia and anoxia.In order to find more effective compounds,we designed and synthesized benzyl thioglucosides which were analogues of S01.The target compounds were synthesized by following steps：2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide was converted to corresponding glucosyl thiol by treating with thiourea and hydrolysis,then reacted with substituted benzyl bromides,benzyl thioglucosides were acquired after removing the acetyl groups.Fourteen target compounds were acquired and their activities were evaluated in vitro on anoxia/reoxygenation injuries model of myocardial cells.The results of primary pharmacological tests indicated that these compounds showed protective effects on anoxia/reoxygenation injuries model of myocardial cells obviously.Three compounds showed stronger effects compared with salidroside,and significant dosage-dependent were observed.To rat primary myocardial cells,the LDH inhibition ratio of S01 and S04 in high dosage were 61.51% and 64.41% respectively,comparatively salidroside was 48.10%.According to the primary SAR analysis,substitutes on benzene rings played important role,not only their type but also their position all can affect the activities.