The Asymmetric Synthesis And Pharmacological Studies Of Danshensu And Its Derivatives

Traditional Chinese Medicine(TCM) is precious cultural heritage of our Chinese nation, long periods of application entitle it with definite clinical effects and comprehensive theoretical systems. With ever-increasing social demand of TCM resources, excessive exploitation and application provide huge challenge to its proper protection. Chemical synthesis is an effective way to tackle and protect the exhaustible resources of TCM. Danshensu, [R]-(+)-3-(3,4-dihydroxyphenyl) lactic acid, is one of the main hydrosoluble active ingredients of Salvia miltiorrhiza Bge.(Danshen), it exhibits diverse pharmacological activities such as anti-coagulant, anti-inflammatory, anti-cancer, anti-atherosclerosis, anti-oxidation, cardioprotection. However, Danshen has a low DSS content(approximately 0.5%), in addition, DSS has high water-solubility, low oral bioavailability, short half-life and structural instability caused by phenolic hydroxyl and α-hydroxy carboxylic acid. Therefore the chemical synthesis of DSS and its derivatives presents promising research value and application prospect. DSS was synthesized by asymmetric transfer hydrogenation, as well as esterification modification of α-hydroxy carboxylic acid were accomplished based on the structure of DSS. Finally the effects of DSS and its derivatives on hemorheology in acute blood stasis model of rats were investigated.In my subject, 3-(3,4-dihydroxyphenyl)-2-oxopropanoic acid could be facilely attained by the Knoevenagel condensation of protocatechualdehyde followed by hydrolysis in 1mol/l hydrochloric acid and acetone. Eventually, the desirable target DSS was synthesized through the asymmetric transfer hydrogenation of α-keto acid employing benzylquinine chloride as the catalyst, DSS sodium was the stable form of DSS, which was testified by 1H NMR. Moreover, a series of benzyloxazoles were synthesized by the Knoevenagel condensation of benzaldehyde, anisaldehyde and vanilline respectively.In terms of esterification modification of α-hydroxy carboxylic acid in DSS, DSS isopropyl ester and ethyl ester were prepared, which was testified by 1H NMR.Finally, the effects of DSS and its derivatives(ethyl ester and isopropyl ester) 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 DSS-ethyl ester has an advantage of improving hemorheology-related indicators over DSS and DSS- isopropyl ester.