Synthesis Of 2,3-(3’-aminoformyl Pyrazole) Fused Lithocholic Acid Derivatives And Their Inhibitory Activities Against Protein Tyrosine Phosphatase 1B

Steroidal compound lithocholic acid is a kind of secondary bile acid that widely exists in bile of higher vertebrate animals. Lithocholic acid and its derivatives possess various bioactivities, such as antifungal effect, antiviral effect, antitumor effect, reducing cholesterol levels, treating cholelithiasis, liver diseases and daibetes mellitus, etc.As a negative regulatory factor in the insulin signaling pathway, protein tyrosine phosphatase 1B(PTP1B) is regarded as a potential target for treatment of daibetes. Our previous research found that lithocholic acid possessed a mild PTPIB inhibitory activity, and its 2,3-heterocycle-fused derivatives had an obviously increased inhibition and high selectivity over homologous enzyme TCPTP.On the basis of our previous research, this thesis chooses 2,3-(1-fluorophenyl pyrazole) fused lithocholic acid amide derivative as the basic skeleton, in order to discover novel PTPIB inhibitors with higher activity and better selectivity.1、With hyodeoxycholic acid as the starting material, the important intermediate 4, 4-dimethyl lithocholic acid derivative (compound 1-55) was successfully prepared via six-step reaction including esterification, substitution, elimination, oxidation and methylation reaction. Two compounds have been designed and synthesized to facilitate introducing other functional groups to the pyrazole.2、Based on above-mentioned compounds, nine 3-amide compounds have been synthesized through some further modification. The result of PTPIB inhibitory activity tests show that most of this series of compounds exhibit certain inhibitory effect (1.66 μM ～4.98 μM), while piperidine amid compound has a poor inhibition to the enzyme.3、The former research has found that 23-COOH might contribute to increasing the activity via interacting with the catalytic active site of PTPIB. Therefore, xidation reactions have been carried out to transform 24-OH to 23-COOH, and seven compounds have been synthesized. The bioactivity tests are still in progress.This research provides an inexpensive and efficient approach for generating of lithocholic acid derivatives, synthesizes a series of novel compounds and discusses their structure-activity relationship, providing a new skeleton with high activity for the study of PTPIB inhibitor which can be used in further research and development of antidiabetic agents.