Potent inhibition of protein tyrosine phosphatases by copper complexes with multi-benzimidazole derivatives

Abstract

A series of copper complexes with multi-benzimidazole derivatives, including mono- and di-nuclear, were synthesized and characterized by Fourier transform IR spectroscopy, UV-Vis spectroscopy, elemental analysis, electrospray ionization mass spectrometry. The speciation of Cu/NTB in aqueous solution was investigated by potentiometric pH titrations. Their inhibitory effects against human protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2), srchomology phosphatase 1 (SHP-1) and srchomology phosphatase 2 (SHP-2) were evaluated in vitro. The five copper complexes exhibit potent inhibition against PTP1B, TCPTP and PTP-MEG2 with almost same inhibitory effects with IC(50) at submicro molar level and about tenfold weaker inhibition versus SHP-1, but almost no inhibition against SHP-2. Kinetic analysis indicates that they are reversible competitive inhibitors of PTP1B. Fluorescence study on the interaction between PTP1B and complex 2 or 4 suggests that the complexes bind to PTP1B with the formation of a 1:1 complex. The binding constant are about 1.14 × 10(6) and 1.87 × 10(6) M(-1) at 310 K for 2 and 4, respectively.

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

“…The three copper complexes exhibited potent and almost same inhibition against PTP1B and SHP-1(IC 50 values in range of 0.15-0.31 μM), about 2-fold stronger than against PTP-MEG2 (IC 50 values from 0.35 to 0.68 μM). The inhibition potency of the three copper complexes against PTP1B was similar to the previously reported dinuclear copper complex of [Bis(diethyl(propane-1,3-diylbis(azanediyl))bis(phenylmethylene)diphosphonate)dicopper(II)] and copper-amino acid complexes [20] as well as copper complexes with multi-benzimidazole derivatives [25], but slightly weaker than copper complexes of Schiff base ligands containing 3,5-substituted-4-salicylideneamino-3,5-dimethyl-1,2,4-triazole which strongly inhibit PTP1B with IC 50 from 0.038 to 0.091 μM [26]. However, they displayed about 10-fold weaker inhibition against TCPTP (IC 50 from 1.81 to 3.05 μM), and almost no inhibition against SHP-2 (IC 50 N 100 μM), differing from the copper complexes with multi-benzimidazole derivatives which exhibited about 10-fold weaker potency against SHP-1 than over PTP1B, TCPTP and PTP-MEG2 [25] and copper complexes of Schiff base ligands containing 3,5-substituted-4-salicyl-ideneamino-3,5-dimethyl-1,2,4-triazole which had 3-4 fold selectivity against PTP1B over TCPTP and PTP-MEG2, and 3-9 fold over SHP-1 [26].…”

“…As copper is an essential metal element with the third abundance in mammalian, and copper complexes have been demonstrated to induce apoptosis of various cancer cells and are expected a promising alternative to overcome the side effects and toxicities of platinum-based antitumor drugs [22][23][24], their potent PTPs inhibition attracts our great interest. We find copper complexes with Schiff base ligands containing 3,5-substituted-4-salicylideneamino-3,5-dimethyl-1,2,4-triazole or multibenzimidazole derivatives are potent PTPs inhibitors with different inhibition ability against different PTPs [25,26], displaying some selectivity. Wide and deep investigation on copper complexes inhibiting different PTPs will help to screen selective copper-based inhibitors over individual PTP and develop copper-based therapeutic drugs.…”

Protein Tyrosine Phosphatase Inhibition by Metals and Metal Complexes

“…The dinuclear copper complexes with organic claw ligands 26-28 exhibit almost the same inhibition of PTP1B and SHP-1, with IC 50 values in a range of 0.15-0.31 lM, *2-fold stronger inhibition than their inhibition of PTP-MEG2 and 10-fold stronger than their inhibition of TCPTP (66). Although the copper complexes with multibenzimidazoles 29-33 have almost the same inhibitory effects on PTP1B, TCPTP, and PTP-MEG2, with IC 50 values from 0.12 to 0.25 lM, they display about a 10-fold weaker inhibition of SHP-1 (61). In contrast, the dinuclear copper complex 34 potently and selectively inhibits TCPTP, with an IC 50 of 0.03 lM, *10-fold stronger than its inhibition of PTP1B, 41-fold stronger than its inhibition of HePTP, 34-fold stronger than its inhibition of SHP-2, and 3 orders of magnitude stronger than its inhibition of SHP-1.…”

“…Vanadate and vanadium complexes are potent PTP inhibitors and efficiently lower blood glucose levels, such as bis(ethylmaltolato)oxovanadium(IV) (BEOV), a bis(maltolato)oxovanadium(IV) (BMOV) derivative, selected for phase 1 and 2 clinical trials (92,102,103,113). The model of PTP inhibition by vanadium compounds is reversible rather than an irreversible oxidation of the catalytic cysteine-SH group (37, 43,61,64,78,120). The inhibitory abilities of most vanadium complexes (Fig.…”

2-[(E)-(4-Bromophenyl)iminomethyl]-4-chlorophenol

“…For background to the biological activity of Schiff bases, see: Akmal et al (2007); Li et al (2007Li et al ( , 2011 ;Lu et al (2011); Ma et al (2011); Rehmana et al (2008); Ritter et al (2009) ;Vanco et al (2008); Yuan et al (2009Yuan et al ( , 2010. For related structures, see: Ardakani et al (2011).…”