Synthesis And Bioactivity Evaluation Of Ursodeoxycholic Acid And Its Derivatives

Ursodeoxycholic acid is widely used in clinical as first-line drug for its safety and general benefits for liver and bile.By far,ursodeoxycholic acid is the medicine proved by FDA for treating Primary Biliary Cirrhosis.It is also a common prescription for different liver functional diseases combined with other medicine.Though it has huge market value,most of the market is held by foreign pharmacy.Thus,developing a novel and competitive method to prepare ursodeoxycholic acid is highly demanded.Colorectal cancer is the third most common incident cancer worldwide.Recently,as economy booming in our country,the eating habit of people starting to contain more fat and less fiber,which leads to higher risk of colorectal cancer.Traditional anti-colorectal cancer drug generally accompanied with high cell toxicity towards normal cell.Besides,they can barely suppress the recurrence of carcinoma.It is of great importance to develop novel drugs against colorectal cancer.Based on previous study,we choose cholic acid as start material to prepare ursodeoxycholic acid.After the selective protection of 3α-OH,selectively oxidize 7α-OH,esterification,12-OH elimination,hydrolysis,and stereospecific hydrogenation,ursodeoxycholic acid is prepared with high yield of 78% in 7 steps.Besides,we successfully synthesis 37 novel derivatives of ursodeoxycholic acid,mainly transformed the 7-OH group into amides as well as discuss the 11,12 position and 24 position.As we synthesis the derivatives,several biological tests were performed to examine the biological activity of them.After several arounds of tests,we came to the structure activity relationship about these derivatives,among these,compound 49 shows high inhibition of 3 different colorectal cancer cell lines and relatively low toxicity towards HAF cell line.