The Synthesis Of Silybin Derivatives And Preliminary Evaluation Of Liver-protecting Bioactivity

Globally,the incidence and prevalence of NAFLD and NASH have risen sharply.NASH can develop into end-stage liver disease and liver cancer that require transplantation,greatly increasing the burden on the global medical system,so there is an urgent need for effective treatment strategies.But so far,the US Food and Drug Administration(FDA)has not approved any drugs for the treatment of NASH.Many drugs for NAFLD with different pathogenic pathways are under study,but only a few drugs have confirmed their efficacy in phase III clinical trials,but there are still some unavoidable adverse reactions.Silybin is an extract of Silybum marianum,which has been used to treat liver diseases for more than 2,000 years.Modern clinics have also proven its high safety,low side effects,and good tolerance in humans.Silybin is used in various liver diseases,especially chronic liver disease,cirrhosis and hepatocellular carcinoma.The limiting factors for using silybin are its low solubility in water,low bioavailability,and poor intestinal absorption.To improve this,there have been many studies on the modification of its results,but the structure of silybin Most of the researches on modification and structure-activity relationship only focus on single or multiple hydroxyl groups,which has limited effect on their activity,so it is urgent to carry out effective structural modification.On the basis of summarizing the current synthesis method and structure-activity relationship of silibinin,and designing a reasonable synthetic route,the second chapter of this paper uses cheap compounds as starting materials,and 13 total synthesis Silybin derivatives to discover NAFLD therapeutic drugs with more hepatoprotective activity and low toxicity.The goal of the synthesis of derivatives in this chapter is designed to open the D ring of silibinin,and reduce the carbonyl group on the flavonoid ring to a hydroxyl group or further reduce the hydroxyl group to a methylene group.On this basis,the E of silibinin is designed A compound in which the cyclic benzene ring is substituted with a pyridine ring.The entire synthetic route has high yield,few by-products,easy post-processing,and has the conditions for industrial large-scale production.In Chapter 3 of this paper,the zebrafish fatty liver model induced by thioacetamide was used to evaluate the activity of some compounds synthesized in Chapter 2 to inhibit liver steatosis.Compared with the silybin control group,at the same concentration,All test compounds showed higher activity to inhibit liver steatosis,and when the test compound concentration reached 200 μM,the inhibitory rates of compounds 3a and 4m exceeded 100%.The results of this paper provide reference and basis for further activity studies,and open up new ideas for structural modification of silybin.