Synthesis And Vasodilative Activity Of Cryptotanshinone Derivatives

Salvia miltiorrhiza Bge is a traditional Chinese medicine used to treat cardiovascular diseases commonly.Cryptotanshinone is the major lipid-soluble components of Salvia miltiorrhiza which has several important functions including anti-oxidant,diastoling blood vessels.But its water solubility is so poor which is difficult to enter the internal circulation system.Therefore,it is structurally modified-mainly by hybridization of cryptotanshinone and water-soluble benzoic acid compounds to obtain derivatives with improved overall polarity,enhanced activity and increased target to exert synergy.An arterial circulatory perfusion model was used to detect the vasodilation activity of these derivatives.1.The synthetic study of cryptotanshinone derivatives.In the solvent of chlorobenzene,2,2,6,6-tetramethylpiperidine-1-oxyl(TEMPO)as an electron transfer carrier,The cryptotanshinone was combined with ben-acid compounds to obtain 42 new cryptotanshinone derivatives(17,18,19-trimethyl-1,2,3,4-tetrahydrophenanthene-[13,14-b]dihydrofuran-11,12-dione-1-benzoate DCT-01-01;17,18,19-trimethyl-1,2,3,4-tetrahydrophenanthrene-[13,14-b]dihydrofuran-11,12-dione-1-phenylacetate DCT-01-11;17,18,19-trimethyl-1,2,3,4-tetrahydrophenanthrene[13,14-b]dihydrofuran-11,12-dione-1-phenylpropionate DCT-01-20 and other derivatives),and preliminary analysis of the effect of different ben-acid compounds on the reaction yields:(1)The yield of the reaction decreases with the elongation of the carbon chain of the ben-acid compounds;(2)Comparing the derivatives of the benzoic acid series,it is found that the yield of the electron-donating group in the meta position is high,and the yield of the electron-withdrawing group in the ortho and para positions is high;(3)Comparing the derivatives of the phenylacetic acid series,it is found that the yield of the electron donating group in the ortho and para positions is high,and the yield of the electron-withdrawing group in the meta position is high.This may be related to the stability of the carboxyl anion and the steric hindrance.At the same time,the optimalconditions for the derivatization of cryptotanshinone were also determined,and the product obtained after the reaction of each acid with cryptotanshinone was a diastereomer,which was determined by NMR,MS,X-ray crystal diffraction,optical rotation.The C-1 of the less polar product in the body is in the "S" configuration,and the C-1 of the more polar product is in the "R" configuration.2.The protective effects on the diastolic activity of thoracic aorta rings in rats.Rat thoracic aorta ring perfusion model was used to detect the activity of cryptotanshinone and its derivatives(1×10-5 M)on NE(1×10-6 M)pre-contracted rat thoracic aorta rings;It was found that the 42 derivatives have no significant increase in the activity of the vasomotor induced by NE compared with the cryptotanshinone.By comparing the pharmacological activity results of all the derivatives,the following analysis can be preliminarily obtained:(1)The pharmacological relaxation activity of the derivatives with benzoic acid and phenylacetic acid as the mother core is equivalent;(2)In the diastereomers,the relaxation activities of most of the C-1 "R" configuration derivatives is slightly stronger than the relaxation activities of the corresponding C-1 "S" configuration derivatives.In this thesis,the synthesis of cryptotanshinone and ben-acid compounds was studied for the first time.42 new cryptotanshinone derivatives were obtained,the effects of different ben-acids on the reaction yields were analyzed and the steric configuration of each derivative was determined.Although the vasodilation activities were not significantly improved,the polarity of the synthesized derivatives was improved;Moreover,preliminary myocardial cell protection experiments showed that some derivatives have a good effect on cardiomyocytes than cryptotanshinone.This study provides a reference value for the further derivatization of cryptotanshinone.