Design And Synthesis Of Cholic Acid And Sulfonamide Derivatives And Their Application In Liver Protection

Chronic liver disease is a common clinical pathological condition.The course of chronic liver disease can be developed gradually from early liver injury and liver fibrosis to liver cirrhosis,portal hypertension,even liver cancer.With the development of the disease,mortality rate and cost of treatment will increase gradually.Studies have found that liver injury and liver fibrosis are reversible.The effective treatment will be of great significance for treatment of chronic hepatitis and prevention of liver cirrhosis.Therefore,the synthesis of compounds which can protect liver has important clinical therapeutic value.Bile acids are a group of acidic steroids with peculiar physical-chemical and biological characteristic.In order to investigate the structure-activity relationship of bile acid oligomers,five different series of bile acid dimers were designed and synthesized using ursodeoxycholic acid,chenodeoxycholic acid,obeticholic acid and different series of connecting linkers.The activity of inhibiting hepatocyte apoptosis in vitro was quantified by the activity of caspase3/7.Most of bile acid oligomers displayed the activity of inhibiting hepatocyte apoptosis.The compounds 1a,1e,2a,and 5a exhibited substantial anti-apoptosis activity with inhibition ratio of 75.60%,88.56%,83.25%,and 105.24%,which were better than positive control tauroursodeoxycholic acid with inhibition ratio of 40.94%.Results revealed that ursodeoxycholic acid and chenodeoxycholic acid oligomers exhibited potency in inhibiting hepatocyte apoptotic.In addition,linker may also affect activities of target compounds.Compounds with shorter linkers such as 1,2-ethanediamine,N,N’-dimethyl-1,2-ethanediamine,and 1,2-ethanediol exhibited better activity than compounds with longer linkers.Compound DM-1 is a sulfonamide which can inhibit liver fibrosis obtained by previous work.We designed and modified the DM-1 by replacing a partial substituent segment and b partial substituent segment which connected with sulfonamide respectively.The synthesis obtained two series of new sulfonamides by strategies of skeleton transformation and bioelectronic transformation.Single luciferase reporter gene detection system was used to detect antifibrotic activity of target compounds in vitro.Most of the compounds in part A displayed anti-fibrosis activity in vitro.Compounds DO-1、DM-5、DP-1、DP-4、DP-6 and DP-7 exhibited substantial anti-fibrosis activity with the inhibition ratio of 37.41%,30.1 5%,33.76%,38.86%,30.54 and 33.15%.The antifibrotic activity of target compounds in part B is being determined.Results revealed that derivatives in part A with electron-absorbing substituent exhibit better activity than that of derivatives with electron donor substituent,and derivatives with para-substituted show better activity than that of ortho-and meta-substituted derivatives.In this dissertation totally 107 compounds have been synthesized,including 54 target compounds,56 of them have been not reported in literature yet.Their structures were characterized by 1H NMR and MS spectra,and some of the target compounds were further comfirmed by HRMS and 13C NMR spectra.