Abstract:
A novel series of functionalized biaryls was designed and synthesized using ketene-S,S-acetal as useful synthon followed by carbanion-induced ring transformation of functionalized lactones. Among various synthesized compounds, two biaryls 6b and 6c showed inhibition against in vitro PTP-1B assay possibly by interacting with amino acid residues Lys120, Tyr46 through hydrogen bonding and aromatic-aromatic interactions, respectively. These compounds showed improved glucose tolerance, fasting as well as postprandial blood glucose, serum total triglycerides, and increased high-density lipoprotein-cholesterol in SLM, STZ, STZ-S and C57BL/KsJ-db/db animal models. The bioanalysis of 6b and 6c revealed that like insulin, the compounds increased 2-deoxyglucose uptake in rat skeletal muscle cells (L6 myotubes). The compound 4'-bromo-2,3-dimethyl-5-(piperidin-1-yl)biphenyl-4-carbonitrile 6b significantly up-regulated the genes related to the insulin signaling pathway, including IRS-1, Akt2, PIK3CG and glucose transporter-4 (GLUT-4) gene in muscle tissue of C57BL/KsJ-db/db mice. Furthermore, it was observed that the compound 6b up-regulated PPARα, UCP2 and HNF4α, which are key regulator of glucose, lipid, and fatty acid metabolism. Western blot analysis of the compound 6b showed that it significantly increased the phosphorylation of p-38 MAPK and ameliorated glucose uptake in C57BL/KsJ-db/db mice through the AMPK-p38 MAPK-GLUT4 pathway.
