title: Dinuclear copper complexes of organic claw: potent inhibition of protein tyrosine phosphatases.
abstract: 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(5)L1), chloro (H(5)L2) and bromo (H(5)L3)): [Cu(2)NaL1(H(2)O)(2)] (1), [Cu(2)HL2(H(2)O)(2)] (2), [Cu(2)NaL3(H(2)O)(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 0.31μM, 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.
authors.affiliation: Institute of Molecular Science, the Key Laboratory of Chemical Biology and Molecular Engineering of Education Ministry, Shanxi University, Taiyuan, 030006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.forename: Liping
authors.initials: L
authors.lastname: Lu
authors.forename: Miaoli
authors.initials: M
authors.lastname: Zhu
authors.forename: Qingming
authors.initials: Q
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Caixia
authors.initials: C
authors.lastname: Yuan
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Wu
authors.forename: Shu
authors.initials: S
authors.lastname: Xing
authors.forename: Xueqi
authors.initials: X
authors.lastname: Fu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Mei
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
mesh_terms: D000147:Acids, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003001:Cloning, Molecular; D003300:Copper / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011199:Potentiometry; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D014169:Transformation, Bacterial; D014961:X-Ray Diffraction
chemical_list: D000147:Acids, Heterocyclic; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D003300:Copper; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; C447615:PTPN9 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D054558:Protein Tyrosine Phosphatases, Non-Receptor