Study On Biological Evaluation And Primary Structure-activity Relationship Of Danshensu Derivatives

Angina is a common symptom of ischemic heart disease.coronary.It's a clinically important disease and a syndrome complex of acute myocardial ischemia caused by insufficiency of aeteria coronaria.Myocardial ischemia is the fundamental pathophysiology change of angina pectoris,namely myocardial oxygen supply and demand out of balance,the demand is greater than the supply.Danshensu is the main active one of Salvia miltiorrhiza water-soluble ingredients.It is an important indicator of one of the ingredients of Dan Shen agents with a wide range of pharmacological effects,such as the dilation of blood vessels,increase coronary blood flow,prevention of myocardial ischemia and hypoxia,anti-thrombosis.One important pharmacological activity-myocardial protective mechanism contains calcium antagonism,free radical scavenging,activation of inward rectifier K+ channels of myocardial cells,resistance to the Peroxynitrite oxidation,inhibition of cardiac hypertrophy,and reduce the increase of abnormal proteins in the myocardial cells.However,due to the nature of the structure in the adjacent two phenolic hydroxyl and a-hydroxy carboxylic acid,danshensu is very unstable,easily oxidized,poor fat-soluble,they can not maintain an effective plasma concentration.In order to find new,efficient,stable anti-ischemic drugs at the same time in order to study their structure-activity relationship,our group introduced amide,amide alcohols,alkyl thiol substituent and heterocyclic systems to Danshensu based on the structural characteristics of it.We have synthesized 89 derivatives in the early research.On the basis of this,we put these derivatives against myocardial cells hypoxia reactive screening test,and pick the 12 derivatives anti-platelet aggregation test,according to the results to infer the preliminary relationship of the structure-activity.The activity test showed that;most of the compounds have a protective effect on hypoxic injury of myocardial cells.21 compounds in their protective effect can reach about 50%and more than;The effectiveness of 23 compounds,on the concentrations of test set,are better than Danshensu.Anti-platelet aggregation test results show that 7 compounds have better activity than other,the two of which are better than Danshensu in both models:zc-wqy-23 zc-wqy-55.This study combines the activity data from two models and design ideas,initially speculated that the relationship between structure and activity are as follows:(1)Phenolic hydroxyl on Danshensu benzene ring can be transformed,the substituent species,quantity,location can affect the activity of the compounds.The groups can synergia or increase compounds stability are CH3O-and-OCH2O-The groups may lead to reduce the activity of compounds are BnO-,CL-,Br-,F-,NO2-.The radical N(CH3)2-has no significant effect to activity.(2)When ?-OCH3 replaced a-OH in Danshensu,the activity of anti-myocardial hypoxia of derivatives did not increase.(3)The thiazolidinedione ring replaced the lactate structure in Danshensu can discrease the activity,indicating that the the thiazolidinedione ring structure is not a synergistic groups.(4)Of the 10 amide alcohol which replace the hydroxide radical of the carboxylic acid,there may be 5 synergies groups,but the structure-function relationship needs further testing.(5)Of the 10 amide groups which replace the hydroxide radical of the carboxylic acid,there may be 3 synergies groups,suggesting carbon chain length on the N may be better in four.(6)When the hydroxide radical of the carboxylic acid was replaced by amide,benzyloxy,and thiazolidinediones,the derivatives can improve the liposolubility.