Protein Tyrosine Phosphonate-1B Inhibition By Oxovanadium, Copper, Zinc Complexes Of Small Bioligands

Diabetes and its syndrome have serious effects on human health. With the advance of modern science and technology, people have acquired a deeper understanding of Diabetes.Recent researches indicate that Protein-tyrosine phosphatese 1B (PTP1B) plays a critical role in regulating body weight, glucose homeostasis, and energy expenditure by acting as a key negative regulator of insulin receptor and leptin receptor mediated signaling pathways and merged as an attractive target for the treatment of type 2 diabetes.Trace element vanadium is demonstrated to have insulin-like effects, including their ability to reduce blood sugar and fats. However, inorganic vanadium salts exhibit poor gastrointestinal absorption and side effects. Relatively, organic-vanadium compounds, which are more lipophilic than inorganic vanadium salts, can elevate the bioavailability. Moreover, organic-vanadium compounds exhibited higher insulin-mimetic activity compared to inorganic vanadium. When vanadium salts or vanadium complexes enter the body, they may undergo ligand exchange with small bioligands such as amino acids, forming in situ vanadium complexes with these ligands. So, the PTPs inhibitory effects of vanadium complexes with small bioligands attracted our interest. The PTP1B inhibition of a series of vanadium compounds with small bioligands were performed. Furtherly, the inhibition of bioligands with zinc and copper compounds were compared under similar conditions.1. A Na2[VO(Glu)2(CH3OH)]·H2O complex was synthesized and characterized by elemental analysis,IR spectrum,electrospray ionization mass spectrometry and potentiometer titration, then the Structure was deduced. The results show that species of powdered is consistent with which in solution.2. The IC50 values of amino acids-VO(Ⅳ) complexes are between 0.13 and 1.05μM, showing high potency as PTP1B inhibitors. These complexes can slightly selectively inhibit PTP1B over other PTPs, such as HePTP,TCPTP,SHP-1. Compared with the amino acids-VO(Ⅳ) compounds, the small molecular organic oxovanadium compounds show slightly weaker inhibition against PTP1B with IC50 values of 0.29 to 21.49μM. The kinetics analysis suggests that Glu-VO(Ⅳ) inhibits PTP1B in a competitive manner. Fluorescence spectroscopic investigation shows the compound can bind to PTP1B with the formation of a 2:1. The experimental result indicated that the quenching belongs to static fluorescence quenching type. The thermodynamic parameters determined from the van't Hoff equation demonstrate that hydrophobic force and electrostatic attraction are the dominant intermolecular forces in stabilizing the complex.3. The PTP1B inhibiting activities of the zinc and copper compounds with same ligands were also investigated. The abilities of PTP1B inhibition of amino acids-copper compounds are very slightly weaker than oxovanadium compounds but obviously stronger than the zinc compounds. Glu-Zn(Ⅱ) inhibits PTP1B competitively. The binding numbers is 1 and the order of formation constant is 106. This result suggests there is some difference in the interaction of Glu-Zn(Ⅱ) with PTP1B and Glu-VO(Ⅳ) with PTP1B.