Synthesis And Activity Study Of The Derivatives Of Silybin Based On Mannich Reaction

Silybin has been used for more than 2000 years to treat liver disorders.In addition to the treatment of acute and chronic hepatitis,liver cirrhosis and other liver diseases,it can also be used in the aspects of depression,blood lipid reduction,protection of heart and other diseases.However,the bioavailability and therapeutic efficiency of silybin were limited by its poor solubility.This is the main reason why silybin pharmacological action is difficult to be applied clinically.To solve this problem,the scholars at home and abroad have carried out extensive studies on physicochemical properties and structural modification by means of various preparation techniques or chemical methods,and have obtained a certain achievement.This study carried out a series of studies on the synthesis of silybin Mannich base derivatives by Mannich reaction for the first time.All the structures of new Mannich base derivatives of silybin were characterized by ¹H NMR and ESI-MS and their protective action on CCl₄ induced liver injury in mice were investigated.Pharmacokinetic characteristics of rats were preliminarily investigated by pharmacokinetic experiments.The main contents and results are as follows:In chapter 1:This study firstly investigated the synthesis conditions of the 2,3-dehydrosilybin compound.Then the synthetic 2,3-dehydrosilybin and silybin were used as the leading compounds for investigating the synthesis conditions of Mannich base derivatives of silybin.A series of Mannich base derivatives of silybin were designed and synthesized.The structural of the target compounds were characterized by ESI-MS,¹HNMR methods.In chapter 2:The protective action of SLB-DEA and DHSLB-DPI on CCl₄ induced liver injury in mice were investigated.The changes of alanine aminotransferase（ALT）,aspartate transaminase（AST）,lactate dehydrogenase（LDH）,total cholesterol（TC）and triglyceride（TG）were determined and the histopathological changes in liver tissues were observed.The results showed that pretreatment with a higher dosage of DHSLB-DPI(40mg·kg^-1)prevented CCl₄-induced liver injury as indicated by the reduced levels of ALT,AST,LDH and TG.Meanwhile,liver histopathological improvement was observed in other groups in comparison with model group.The pharmacokinetics study in rats showed that the relative bioavailability of SLB-DEA and DHSLB-DPI were 172.5%and 259.8%compared with silybin.All the results indicated that SLB-DEA and DHSLB-DPI could protect against liver injury well induced by CCl₄ and the relative bioavailability were significantly increased,which could be worthy of further investigations of their druggability.In chapter 3:With the silybin and 2,3-dehydrosilybin as the lead compound,and cholate as the liver targeted group,Four silybin Mannich base derivatives of liver targeted were designed and synthesized.The structural of the target compound was characterized by ESI-MS,¹HNMR methods.The protective action of SLB-DCA and SLB-DCA on CCl₄induced liver injury in mice were investigated.The results showed that SLB-DCA and SLB-UCA could significantly reduce the levels of ALT,AST and LDH in the serum of mice.Meanwhile,compared with silybin,SLB-DCA and SLB-UCA could depress the TG content of liver cells in mice,and showed a good pharmacological effect on improving lipid metabolism in mice.