Design,Synthesis And Biological Evaluation Of Anti-diabetic Activities Of 4-fluoro Substituted Pyrazole Derivatives As Potent Glucagon Receptor Antagonists And Novel Methodology To Construct Pyrroloindolone Scaffold

This dissertation for Master degree focuses on the design,synthesis,and biological evaluation of a novel series of 4-fluoro substituted pyrazole derivatives as potent glucagon receptor(GCGR)antagonists based on the traditional medicinal chemistry,modern organic synthesis,and bioassay.In addition,a novel synthetic methodology approaching to pyrroloindolone scaffold has been achieved via ruthenium(Ⅱ)-catalyzed C—H bond activation of redox-neutral[3+2]annulation of indoles with internal alkynes.Chapter 1 presents the design,synthesis,and biological evaluation of anti-diabetic activities of a novel series of 4-fluoro substituted pyrazole derivatives as potent glucagon receptor antagonists.Diabetes is one of the largest health problems of human which influences people’s health severely.Glucagon binds to the glucagon receptor and triggers a signal transduction cascade to stimulate the hepatic glucose production via glycogenolysis and gluconeogenesis.In type 2 diabetes with fasting and postprandial states,inappropriately elevated glucagon levels lead to excessive hepatic glucose output.Therefore,a novel series of GCGR antagonists was designed as potential anti-diabetic agents.Twenty-eight novel 4-fluoro substituted pyrazole compounds(A1-A28)were designed and synthesized and all these compounds were biologically evaluated to verify the anti-diabetic activity.The results indicated that nine compounds displayed GCGR binding with IC50less than 100 nM.Among these tested compounds,A20(GCGR binding IC50=37 nM;cAMP response IC50=102 nM)and A28(GCGR binding IC50=33 nM;cAMP response IC50 = 329 nM)were proved to be the best two compounds,which displayed good biological activity against the GCGR binding and cAMP functional activity.Enantiopure compounds R-A20 and S-A20 were resolved from the racemic A20 and interestingly,compound S-A20 showed good activity against the GCGR binding(IC50=33 nM)and cAMP functional activity(IC50=75 nM),which is in a comparable level of the positive control MK-0893(GCGR binding IC50=19 nM;cAMP response IC50=60 nM).Chapter 2 presents a novel synthetic methodology to construct pyrroloindolone scaffold via ruthenium(Ⅱ)-catalyzed C-H bond activation of redox-neutral[3+2]annulation of indoles with internal alkynes.Pyrroloindolone scaffold is an integral part of many biologically active natural molecules and pharmaceuticals.Although several approaches have been developed for the synthesis of pyrroloindolone scaffold,these methods have suffered from scope limitations,poor regio-selectivity,and low yields.A novel method to construct pyrroloindolone scaffold by using the inexpensive Ru as catalyst has been developed and the generated product can be subsequently transformed into trisubstituted α,β-unsaturated ketones,which are hardly accessible through direct C-H coupling.Broad internal alkyne scope includes various aryl/alkyl-,alkyl/alkyl-,and diaryl-substituted alkynes.The reaction was preceeded under milder conditions than the reported methods and it is compatible with various functional groups.The products were obtained in moderate to excellent yields with good to excellent regioselectivity.The method provides an alternative strategy for the construction of pyrroloindolone scaffold.