| Danshensu(DSS,(R)-3, 4-dihydroxyphenyl lactic acid), one of the water-soluble active component isolated from Salvia Miltiorrhiza root is considered to be the main ingredient accounting for DSS bioactivity. DSS has a structure of phenyl lactic acid, bearing two phenol hydroxyl groups and a α-hydroxyl group. The two phenol hydroxyl groups are readily to be oxidized accounting for DSS’s instability. Besides, DSS is difficult to cross lipid membrane due to the strong polar carboxylic group. Although DSS is effective in protecting myocardial cell against damage, its therapeutic effect is weak. The instability, low bioavailability and weak effects limit its use in clinic.In our previous work, we have synthesized series of DSS derivatives, among which, ADTM is effective in preventing cell from oxidative insult induced by hydroperoxide. ADTM significantly reduced infarct size of ischemic heart in rats. Based on previous studies of SAR, in this work, we designed a new series of DSS derivatives with the introduction of bulky groups to the carboxylic position through an ester bond. Meanwhile, the α-hydroxyl groups are substituted by different moieties through an ether bond. The main aim of these modifications was to improve DSS derivatives’ therapeutic effect and stability.We have synthesized 7 DSS derivatives and all of them were characterized by ESI-MS, 1H-NMR, 13C-NMR and elemental analysis. The biological evaluation demonstrated that compound ADT-4 was effective in protecting myocardial cell against oxidative damage caused by hydroperoxide. The protective effect of ADT-4 was even much higher than that of ADTM. The SAR investigation suggested that the introduction of bulky groups at the carboxylic group through an ester contributed to DSS’s improved activity, while modification at the α-hydroxyl group didn’t significantly affect DSS’s activity. The introduction of bulky groups at the carboxylic position didn’t change the metabolic profile of DSS derivatives compared with ADTM. |
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