Dinuclear copper complexes of organic claw: Potent inhibition of protein tyrosine phosphatases

• Published in: Journal of inorganic biochemistry 2011-09, Vol.105 (9), p.1138-1147
• Main Authors: Ma, Ling, Lu, Liping, Zhu, Miaoli, Wang, Qingming, Gao, Fei, Yuan, Caixia, Wu, Yanbo, Xing, Shu, Fu, Xueqi, Mei, Yuhua, Gao, Xiaoli
• Format: Article
• Language: English
• Subjects: Acids, Heterocyclic - chemical synthesis; Acids, Heterocyclic - pharmacology; Chelating Agents - chemical synthesis; Chelating Agents - pharmacology; Cloning, Molecular; Copper - metabolism; Crystallography, X-Ray; Dinuclear copper complexes; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Escherichia coli; Humans; Inhibitor; Kinetics; Ligands; Models, Molecular; Potentiometry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Protein Tyrosine Phosphatases, Non-Receptor - antagonists & inhibitors; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; PTPs; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Selectivity; Signal Transduction - drug effects; Signal Transduction - physiology; Spectrometry, Mass, Electrospray Ionization; Substrate Specificity; Transformation, Bacterial; X-Ray Diffraction
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2011.05.015

Three dinuclear copper complexes of organic claw ligands (2,2′,2″,2‴-(5-R-2-hydroxy-1,3-phenylene)bis(methylene)bis(azanetriyl)tetraacetic acid, R = methyl (H 5L1), chloro (H 5L2) and bromo (H 5L3)): [Cu 2NaL1(H 2O) 2] ( 1), [Cu 2HL2(H 2O) 2] ( 2), [Cu 2NaL3(H 2O) 2] ( 3), have been synthesized and characterized by elemental analyses, infrared spectra, thermo-gravimetric analyses, X-ray diffraction analysis, electrospray ionization mass spectra, pH-potentiometric titration, molar conductivity. Their inhibitory effects against human protein tyrosine phosphatase 1B (PTP1B), T cell protein tyrosine phosphatase (TCPTP), Megakaryocyte protein tyrosinephosphatase 2 (PTP-MEG2), srchomology phosphatase 1 (SHP-1) and srchomology phosphatase 2 (SHP-2) are evaluated in vitro. The three copper complexes exhibit potent and almost same inhibition against PTP1B and SHP-1 with IC 50 values ranging from 0.15 to 0.31 μM, about 2-fold stronger inhibition than against PTP-MEG2, 10-fold stronger inhibition than against TCPTP, but almost no inhibition against SHP-2. Kinetic analysis indicates that they are reversible competitive inhibitors of PTP1B. Molecular docking analyses confirm the inhibition model. Fluorescence titration studies suggest that the complexes bond to PTP1B with the formation of a 1:1 complex. The results demonstrate that copper complexes that are potent PTPs inhibitors but have different inhibitory effects over different PTPs, may be explored as new practical inhibitors towards individual PTP with some specificity. Three dinuclear copper complexes of organic claw ligands (2,2′,2″,2‴-(5-R-2-hydroxy-1,3-phenylene)bis(methylene)bis(azanetriyl)tetraacetic acid) have been synthesized and characterized, which exhibit potent same inhibition against PTP1B and SHP-1, about 2-fold stronger inhibition than against PTP-MEG2, 10-fold stronger inhibition than against TCPTP, but almost no inhibition against SHP-2. [Display omitted]