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Protein tyrosine phosphatase 1B (PTP1B) is known to be implicated in insulin resistance, and inhibitors of PTP1B were supposed to be useful to regulate insulin and leptin signalling pathways. In this report, calix [4] arene mono-and bis-α-ketophosphonic acids were tested in vitro as potential inhibitors of PTP1B. New calix [4] arene-based inhibitors were synthesized through the reaction of corresponding acyl chlorides with triisopropylphosphite followed by dealkylation of α-ketophosphonate diisopropyl ester groups. Inhibiting capacity of the synthesized compounds toward PTP1B was higher than that for other protein tyrosine phosphatases such as TC–PTP, LAR, MEG1, MEG2, and SHP2. Kinetic studies showed that the inhibitor can bind to PTP1B in competition with substrate. According to molecular docking results, phosphonate groups of the inhibitors form hydrogen bonds with amino acid residues in the active site. In addition, macrocyclic platform provides hydrophobic and van der Waals contacts with the enzyme.