Ternary oxovanadium(IV) complexes with amino acid-Schiff base and polypyridyl derivatives: Synthesis, characterization, and protein tyrosine phosphatase 1B inhibition

To investigate the structure–activity relationship of vanadium complexes in inhibiting protein tyrosine phosphatase1B (PTP1B), eight mixed-ligand oxovanadium(IV) complexes, [VIVO(SalAla)(NN)] (H2SalAla for salicylidene alanine, NN for N,N′-donor heterocyclic base, namely, 2,2′-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, 3), dipyrido[3,2-a:2′,3′-c]phenazine (dppz, 4)), [VIVO(SalLys)(dpq)] (5), [VIVO(SalLys)(dppz)] (6), [VIVO(SalAsp)(dppz)], (7) and [VIVO(SalTrp)(dppz)] (8)), of which 3–8 are new, have been prepared and characterized by elemental analysis, infrared, UV–visible, electrospray ionization mass spectrometry and conductivity. The molar conductance data confirmed the non-electrolytic nature of the complexes in DMSO solution. The coordination in [VIVO (SalAla)(phen)] (2) was confirmed by X-ray crystal structure analysis. The oxidation state of V(IV) with d1 configuration in 2 was confirmed by EPR. The speciation of VO–SalAla–phen in aqueous solution was investigated by potentiometric pH titrations. The results indicate that the main species are two ternary complexes at the pH range 7.0–7.4. Biochemical assays demonstrate that the mixed-ligand oxovanadium(IV) complexes are potent inhibitors of PTP1B with IC50 values in the range of 62–597 nM, approximately 3–10 fold weaker in potency than those of similar mixed-ligand oxovanadium(IV) complexes of salicylidene anthranilic acid (SAA) derivative with polypyridyl ligands, except complex 8, which exhibits comparable or better inhibition activity than those of the mixed-ligand oxovanadium(IV) complexes of SAA derivative with polypyridyl ligands. The results demonstrate that the structures of vanadium complexes influence the PTP1B inhibition activity. Kinetics assays reveal that complex 2 inhibits PTP1B in a competitive manner.

Graphical AbstractA series of mixed-ligand vanadyl complexes [VIVO(Sal-aa)(NN)] (NN = bpy, phen, dpq and dppz, aa = ala, asp, lys, trp) were synthesized and characterized. All complexes show similar hexacoordinated distorted octahedral structures and display potent inhibitory activity against human tyrosine phosphatase 1B in vitro.Figure optionsDownload as PowerPoint slide