Temperature and solvent structure dependence of VO2+ complexes of pyridine-N-oxide derivatives and their interaction with human serum transferrin

Abstract

The behaviour of the systems formed by VO(2+), 2-hydroxypyridine-N-oxide (Hhpo) and 2-mercaptopyridine-N-oxide (Hmpo) was studied both in solution and in the solid state through the combined application of spectroscopic (EPR and UV-Vis spectroscopy) and DFT methods. The geometry of solid bis-chelated complexes [VOL(2)], with L = hpo and mpo, is square pyramidal, but it can change to cis-[VOL(2)S], where S is a solvent molecule, when these are dissolved in a coordinating solvent. The equilibrium between the square pyramidal and cis-octahedral forms is strongly affected by solvent and temperature. At room temperature, the predominant species is [VOL(2)], which gives a pink colour to the solutions; at lower temperatures, the equilibrium is shifted--partially or completely--toward the formation of cis-[VOL(2)S], which is green. In an acidic environment and in the presence of an excess of ligand, [VOL(2)] can transform into the tris-chelated complex [VL(3)](+), in which vanadium loses the oxido ligand and adopts a hexa-coordinated geometry intermediate between octahedral and trigonal prismatic. 1-Methylimidazole (1-MeIm), which represents a model for His-N coordination, forms mixed complexes with stoichiometry cis-[VOL(2)(1-MeIm)], occupying an equatorial position. In the ternary systems VO(2+)-Hhpo-hTf and VO(2+)-Hmpo-hTf at room temperature and pH 7.4, besides (VO)hTf and (VO)(2)hTf, the mixed species cis-VO(hpo)(2)(hTf) and VO(mpo)(hTf) are observed, with the equatorial binding of an accessible histidine residue. Finally, the contribution of the N-oxide group to (51)V A(z) and A(iso) hyperfine coupling constants, which can be important in the characterisation of similar species, is discussed.

Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients

“…The variable response to the metal salt VOSO 4 may be due to free metal ions quickly binding to various ligands in the serum (such as serum proteins and specifically human transferrin). A series of in vitro studies with both salts and V complexes have shown complexation of the V ion in several oxidation states to the transferrin 23, 24, 75, 76 . Some controversy existed in the early studies because studies with BMOV resulted in an additional V signal 53 .…”

“…Later studies showed in fact that this extra signal was due to excees protein and formation of uncomplexed vanadyl cation. 77 However, since then alternative methods have been used to observe mixed ternary complexes formed from the salts or coordination complexes in the presence of proteins 9, 11, 21, 23, 24, 31–35, 75, 76 . Specifically, in vitro studies demonstrate formation of cis- VO(ma) 2 (human Transferrin), 24 Other protein complexes form including complexes with human serum albumin such as cis- VO(ma) 2 (HSA) and immunoglobin such as cis- VO(ma) 2 (IgG).…”

Behavior of the potential antitumor VIVO complexes formed by flavonoid ligands. 2. Characterization of sulfonate derivatives of quercetin and morin, interaction with the bioligands of the plasma and preliminary biotransformation studies

“…The chemical form with which a vanadium compound reaches the target organs affects the uptake by the cells, which can take place through passive diffusion or be mediated by transport proteins. It was shown that the geometry at the physiological pH of a pharmacologically active VOL 2 compound, where L is a bidentate ligand, can influence the interaction with the proteins, such as transferrin (hTf), albumin (HSA), immunoglobulin G (IgG) or hemoglobin (Hb) [39]: when it is cis-octahedral (cis-VOL 2 (H 2 O)), the equatorial water molecule can be replaced by an accessible His-N to form a species with stoichiometry cis-VOL 2 (Protein), whereas when it is square pyramidal (VOL 2 ) no interaction is expected [37,38,[40][41][42][43][44][45][46][47][48][49][50] …”

“…Indeed, at 298 K only V IV O species in which a protein is coordinated to the metal ion give anisotropic spectra, whereas the compounds in which V is bound to small ligands originate isotropic spectra. Anisotropic signals are obtained at room temperature for several V IV O-protein compounds, as previously reported in the literature [44,47,48,68,[92][93][94][95]. This is due to the fact that the rotational motion of the species human plasma proteins [96][97][98].…”

“…The difference between the two proteins is that apo-hTf is able to bind contemporaneously V IV O 2+ with two residues, whereas for HSA only one group belonging to an accessible residue can coordinate vanadium.The most important result of this study is the detection at room temperature, in the ternary systems with apo-transferrin and albumin, of an anisotropic EPR spectrum for the species VO(que) 2 /VO(que S ) 2 and VO(mor) 2 /VO(mor S ) 2 in which the protein is not directly coordinated to V IV O 2+ ion. Whereas in the systems containing proteins anisotropic signals were revealed only when these latter are coordinated to the metal ion hindering a fast rotational motion of the V IV O species[44,47,48,68,[92][93][94][95], in the systems with que/que S and mor/mor S this observation isexplained assuming that the bis-chelated V IV O complex (VO(que) 2 /VO(que S ) 2 or VO(mor) 2 /VO(mor S ) 2 ) strongly interacts with the protein through a network of hydrogen bonds between the OH groups of the flavonoid derivative and the polar groups present on the protein surface such as carboxylate of Asp and Glu, amide group of Asn and Gln, hydroxy of Ser, Thr and Tyr, guanidine of Arg, amino of Lys and imidazole nitrogen of His. This hypothesis is confirmed by other studies in the literature which describe the interaction of quercetin and other phenolic…”