The Synthesis And Preliminary Pharmacological Studies Of Danshensu-amino Acid Amide Derivatives

Danshensu(DSS) is one of active water-soluble component in Danshen, it exhibits diverse pharmacological activities such as anti-cancer, anti-atherosclerosis, anti-oxidation, cardioprotection. However, because of relatively low content in Danshen(0.5%) and structural distability, the chemical synthesis of DSS and its derivatives possess research value. Moreover amino acids have plentiful activities as well such as trophism, immunoregulation and anti-tumor. On the basis of Medicinal Chemistry Hybridation, several amide between DSS and amino acids derivatives have been designed and synthesized. In addition, the effects of DSS and its derivatives on hemorheology in acute blood stasis model of rats were investigated.DSS-sodium was synthesized from protocatechualdehyde by the reactions of Knoevenagel condensation, hydrolization, asymmetric reduction and salt-forming. Then the corresponding amino acids methyl(ethyl)esters hydrochloride were obtained via thionyl chloride methods through the reaction between phenylalanine, leucine, methionine, aspartic acid and methanol(ethanol). Finally, we try to Danshensu Sodium and amino acid ester hydrochloride in a variety of the amide bond a bond coupling reagent(DCC/DMAP, NMM/IBCF, EDCI/HOBt, EDCI/DMAP) synthesis of a new type of DSS-amino acid amide derivatives. The use of EDCI/DMAP respectively synthesis of Danshensu and phenylalanine methyl(ethyl) ester, leucine methyl ester, methionine methyl ester and aspartic acid dimethyl ester five amide derivatives, their chemical structures have passed characterized by 1H NMR confirmed.Finally, the effects of DSS and its amide derivatives on hemorheology-related indicators(ηb and RI) in acute blood stasis model of rats were investigated. The model can be duplicated after the treatment of adrenaline injected subcutaneously and ice-water bath, then DSS and its derivatives as well as positive control CDDP were administered respectively to test their influences on ηb and RI. Experimental results have shown that compound 10 has an advantage of improving hemorheology-related indicators over DSS and compound 12.