Part One:Designandsynthesisof 6-?ethylchenodeoxycholic Acid And Its Derivatives Part Two:design,synthesis And Biological Activity Of The Derivatives Of Niclosamide

6-alpha ethyl chenodeoxycholic acid(6ECDCA),also known asobeticholic acid,chenodeoxycholic acid 6-ethyl substituted derivatives,is the first farnesoid X receptor selective agonists to enter clinical,by activating FXR in the liver,intestine,kidney and other tissues,inhibit the synthesis of bile acids,increased insulin sensitivity,regulating fat metabolism and glucose homeostasis.Farnesoid X receptor(FXR)belongs to the nuclear receptor superfamily,is mainly expressed in liver,kidney and gastrointestinal tract.As a bile acid receptor FXR through the regulation of a series of gene expression,regulation of bile acid synthesis,transport and metabolism,in bile acid and cholesterol metabolism has an important role and become an important drug targets.As the specificity of FXR agonists,6-alpha ethyl chenodeoxycholic acid extracellular EC50 for 99nmol/L,intracellular EC50 for 85nmol/L,with approximately 100 times higher activity than FXR natural agonists chenodeoxycholic acid.Clinical study results show that the Austempered cholic acid in primary biliary cirrhosis(PBC)and nonalcoholic fatty hepatitis(NASH)has a good therapeutic effect.Has received FDA treatment with liver fibrosis in nonalcoholic fatty hepatitis breakthrough of therapy and in the treatment of primary biliary cirrhosis patients with fast track eligibility,also in the United States and Europe received the treatment in patients with PBC orphan drug status,for the treatment of the old standard drug ursodeoxycholic acid treatment of patients who do not respond adequately to or intolerant,is expected to replace ursodeoxycholic acid treatment status,become the effects of drugs for the treatment of NASH and PBC,field in the treatment of liver diseases show a great application prospect.Structure-activity relationship analysis showed that 6-alpha ethyl chenodeoxycholic acid molecule 6 ethyl and 24 carboxyl group is specific functional groups of its activity.This topic in six ethyl and 24 carboxyl group based,on three hydroxyl of 6-alpha ethyl chenodeoxycholic acid molecules were derived transformation,the introduction of polar amino groups,with carbamate bond as connector,conducive to the selective hydrolysis of liver enzymes,in order to improve the hepatocyte targeting of drugs and at the same time,the amino acids of polar groups to improve water solubility and improved pharmacokinetic properties.On the basis of this,6 amino acid derivatives were designed and synthesized,and the structure of the compound was confirmed by 1H-NMR and ESI-MS.Firstly,the synthesis of the positive control drug 6-alpha ethyl chenodeoxycholic acid were optimized.Reported in the literature 6 alpha ethyl chenodeoxycholic acid synthetic route is long,harsh reaction conditions and need to low temperature and anhydrous and anaerobic conditions,the total yield is low,not easy to put a large number of synthetic system.This paper chooses the chenodeoxycholic acid as the starting material,after oxidation,esterification,etherification of silicon,sub ethylation,reduction and hydrogenation,to obtain the target compounds.By improving the oxidant type and ratio,change 24 carboxyl group protection strategy,abandon harsh anhydrous and anaerobic conditions,and improve the hydrogenation conditions etc..The synthetic route was optimized,improve the intermediate yield,the total yield reached 42%.It can be used as the basis of a large number of synthetic routes.Then to the synthesis of 6-alpha ethyl chenodeoxycholic acid as raw material,on the design of the amino acid derivatives were synthesis and structure elucidation and the activity of related compounds are being tested.This thesis to chenodeoxycholic acid as raw material,through a series of reactions obtained 6 alpha ethyl chenodeoxycholic acid,then its as a lead compound designed and synthesized six amino acid derivatives,and the activity of related compounds are being tested.All the compounds are chemical structure by MS and 1HNMR.Niclosamide is also calledyomesan,and clinicallyused for the treatment of intestinal parasitic infection and effective on a variety of tapeworm.In recent years,a variety of high throughput screening studies have indicated that it is a potential antitumor drug.By inhibiting the signaling pathways of-catenin,m TORC1,STAT3,NF-k B,ROS,Wnt/beta-catenin,and Notch,the inhibition of cell cycle arrest,growth inhibition and apoptosis was induced by the targeting of mitochondria in tumor cells.Many in vitro and in vivo studies have demonstrated that the anti-tumor activity of the chloride,the inhibition of tumor stem cells to make the potential drug for the treatment of cancer.In vitro and in vivo animal experiments proved niclosamide can inhibit tumor cell proliferation,metastasis,and invasion ability,and promote apoptosis of tumor cells,in order to exert the anti tumor cell activity.These characteristics make it possible to be an effective anti tumor in clinical practice.By niclosamide Anshui solution is poor,in the low water soluble lead to its in vivo biological utilization degree is low,in SD rats and oral bioavailability of only about 10%,medicine,relatively low oral bioavailability by degree and the relatively poor water solubility decreases the antitumor effect of niclosamide in clinical application.But the appropriate chemical modification of its,can significantly improve the water solubility and enhance its bioavailability in vivo.Therefore,niclosamide has become a natural source of active drug precursor research potential new.This topic mainly of niclosamide 2 hydroxy of derivative transformation,the introduction of specific and can improve the water solubility of polar groups,to improve the specificity of bioavailability,while increasing its solubility in water,improve niclosamide in human medicine generation of dynamical properties.The introduction of a variety of aliphatic chain carboxyl groups or amino groups in aliphatic chain or oxime groups by 2 hydroxyl ether bond coupling with niclosamide,to improve the solubility and pharmacokinetic characteristics.This thesis to niclosamide as raw material,three groups,15 derivatives were designed and synthesized,7 carboxylic acid derivatives,4 amino derivatives and 4 oxime derivatives,activity of compounds are being tested,all chemical structure by MS and 1HNMR were identified.And the design of derivative compounds were preliminary antitumor activity evaluation.