Synthesis And PTPs Inhibitory Activity Of Oxovanadium And Copper Complexes With Schiff Base Ligands

Protein tyrosine phosphatases (PTPs) involve in the regulation of many cell function, such as cell proliferation, metabolism and cell communication. Many human diseases are related to the dysregulation of PTP activities. Inhibition of PTPs activity can regulate cellular signal transduction by increasing the phosphorylation level of the cell.The study showed vanadium complexes exhibited high insulin-mimetic potential and the performance was related to the inhibition aginst PTP1B. It is worthy of mention that very recent researches show metal-based PTP selective inhibitors exhibit consistent selectivity in cells as in vitro,suggesting in vitro screened metal-based selective PTP inhibitors may work in vivo. Wide investigations of vanadium complexes inhibiting various PTPs and screening PTP1B selective inhibitors are promising.Recently our group reported some copper complexes with several types of ligands, and their inhibitory effects against PTPs were evaluated.In this paper, we designed and synthesized a series of Schiff base derivatives and their oxovanadium and copper complexes as novel, potent and selective inhibitors of PTPs, and further discussed the interaction mechanisms. Main results were obtained as follow:1.A series of oxovanadium and copper complexes with Schiff bases (named H2bhbb, H2chbb, H2nhbb, Hbpmp, Hcpmp, Hnpmp)were synthesized and characterized by elemental analysis, infrared spectra, UV-vis spectroscopy, ESI-MS spectra, EPR spectra and potentiomtreic pH titrations. The coordination in [VIVO(bhbb)(H2O)2]1and Hbpmp(HL4) was confirmed by X-ray crystal structure analysis.2.Oxovanadium complexes1-5{[VIVO(L1)(H2O)2](1),[VIVO(L3)(H2O)2](2),[VIVO(L5)2](3),[VIVO(L4)2](4),[VIVO(L6)2](5)}were tested for their abilities in inhibiting PTP1B, TCPTP, PTP-MEG2, SHP-1and SHP-2. The results show that almost all the five complexes display strongest inhibition against PTP IB, though they exhibit different inhibitory ability over different PTPs. Complexes1and2have slightly stronger inhibitory effects against PTP1B (IC50,0.21-0.23μM) than3-5(IC50,0.69-0.93μM). Complexes2and4show better selectivity to PTP1B. The study of cell extracts shows oxovanadium complexes not only inhibit recombinant PTPs activity but also inhibit cellular PTPs. Kinetics data show complex2inhibit PTP1B, TCPTP and SHP-1with a noncompetitive inhibition mode but a classical competitive inhibition mode for PTP-MEG2and SHP-2.Fluorescence study on the interaction between complex2and PTP1B, TCPTP, PTP-MEG2suggests that the ratio of complex bind to PTPs is1:1.The binding constant are about6.86X105M-1,9.58X104M-1,4.64X104M-1at310K for PTP1B, TCPTP, PTP-MEG2respectively.3.Copper complexes6-10{[Cu(LI)(H2O)](6),[Cu(L2)(H2O)](7),[Cu(L3)(H2O)](8),[Cu(L5)2](9),[Cu(L6)24.5H2O](10-4.5H2O)}exhibit strong inhibitory ability over PTPs but almost no inhibition against SHP-2. Complexes6and7show better selectivity to TCPTP while Complex10show selectivity to PTP1B.Copper complexes have significantly stronger inhibitory effects against PTPs but weaker selectivity than vanadium complexes besides SHP-2. The study of cell extracts shows Copper complexes can inhibit cellular PTPs. Kinetics data show complex2inhibit PTP IB, TCPTP, PTP-MEG2and SHP-1with a noncompetitive inhibition mode.All these results illustrate ligands of complexes influence the inhibtory effects of different PTPs. When complexes with a different metal but the same ligand, there is a great difference in inhibitory effect of PTPs. The results demonstrate that both the structures of complexes and the conformations of PTPs influence PTP inhibition activity.Properly modifying the organic ligand moieties on metal may achieve to screen potent and selective metal-based PTP1B inhibitors.