Total Synthesis And Activity Research Of Danshensu Analogues

Danshen, the dry root of labiatae plants Salvia miltiorrhiza Bunge, has been studied deeply for its chemical compositions, and Danshensu [D-(+)-β-(3,4-dihydroxyphenyl) lactic acid] is the most effective of its water-soluble components. Because of the less content in Danshen, abstraction and purification turned to be more difficult. And the extract was always a mixture of water-soluble components. Thus affecting the quality of the clinical application and further development and sustainable utilization of natural medicine.Chirality is one of the essential attribute of nature, almost all the biological macromolecules are chiral. As chiral drugs enter the human body, pharmacological effects produced by different configurations of drug molecules tend to be different, drugs may be more prominent, also may not change, even the opposite. According to statistics, among the 1800 drugs for clinical use,1026 kinds are chiral drugs, accounted for 57%, there are 61 kinds of drugs listed in the form of single enantiomers. The rest are racemic form. And now 1200 drugs are being developed,820 species of them are chiral drugs,612 species are in the form of single enantiomers, accounted for 51%, this fully shows that chiral drug development has become one of the mainstream of international drug research. The chemical structure of Danshensu contains a chiral carbon. Therefore, to explore the biological activity of different configurations of Danshensu and its derivatives is particularly important.In addition, Danshensu has a very strong water-solubility, due to its phenolic hydroxyl and carboxyl, so that it is difficult to enter the lipid bilayer, and the absolute bioavailability is low when taken orally. Furthermore, the carboxyl can combine with glucuronic acid and then excrete along with the urine, so its half-life is short in the body. Therefore, in order to obtain prodrug with better pharmacokinetic characteristics and more stable space configuration, structure modification must be taken in consideration which will also be good for widely applied in clinical.3,4-dihydroxybenzaldehyde was firstly chosen as the starting material for obtaining racemic Danshensu via main processes of protection of the phenolic hydroxyl group, Darzens condensation, reduction, hydrolysis and deprotection. Secondly, Danshensu ester derivatives with different carbon chain have been totally synthesised by different reagents, aimed at studying the effects of different carbon chain on biological activity, and it also decrease the water-solubility, improve the lipid-water partition coefficient, increase the stability of the compound constructure. Finally, chiral separation of the ester derivatives of Danshensu have been practised in order to explore the differences of pharmacological activities between each chiral enantiomers, which will provide theoretical basis to medicinal properties.Pharmacological experiments with target compounds were determined by MTT and cck-8 methods to test the effects on hypoxic-ischemic myocardial cell activities. Preliminary pharmacological results showed that:1. The pharmacological activity of racemic Danshensu performed higher than that of natural Danshensu; 2. There are differences between activities of each enantiomers; 3. Danshensu ester derivatives performed a better anti-ischemic activity in 100μmol/L than in 25μmol/L; 4. The activity of Danshensu ester derivatives varied along with the ester chain was lengthened.