Luqin Yang

Effect of vanadium(IV) compounds in the treatment of diabetes: in vivo and in vitro studies with vanadyl sulfate and bis(maltolato)oxovandium(IV)

Vanadyl sulfate (VOSO(4)) was given orally to 16 subjects with type 2 diabetes mellitus for 6 weeks at a dose of 25, 50, or 100 mg vanadium (V) daily [Goldfine et al., Metabolism 49 (2000) 1-12]. Elemental V was determined by graphite furnace atomic absorption spectrometry (GFAAS). There was no correlation of V in serum with clinical response, determined by reduction of mean fasting blood glucose or increased insulin sensitivity during euglycemic clamp. To investigate the effect of administering a coordinated V, plasma glucose levels were determined in streptozotocin (STZ)-induced diabetic rats treated with the salt (VOSO(4)) or the coordinated V compound bis(maltolato)oxovandium(IV) (abbreviated as VO(malto)(2)) administered by intraperitoneal (i.p.) injection. There was no relationship of blood V concentration with plasma glucose levels in the animals treated with VOSO(4), similar to our human diabetic patients. However, with VO(malto)(2) treatment, animals with low plasma glucose tended to have high blood V. To determine if V binding to serum proteins could diminish biologically active serum V, binding of both VOSO(4) and VO(malto)(2) to human serum albumin (HSA), human apoTransferrin (apoHTf) and pig immunoglobulin (IgG) was studied with EPR spectroscopy. Both VOSO(4) and VO(malto)(2) bound to HSA and apoHTf forming different V-protein complexes, while neither V compound bound to the IgG. VOSO(4) and VO(malto)(2) showed differences when levels of plasma glucose and blood V in diabetic rodents were compared, and in the formation of V-protein complexes with abundant serum proteins. These data suggest that binding of V compounds to ligands in blood, such as proteins, may affect the available pool of V for biological effects.

Vanadium(IV) and vanadium(V) complexes of dipicolinic acid and derivatives. Synthesis, X-ray structure, solution state properties: and effects in rats with STZ-induced diabetes

Abstract Preparation and characterization of new vanadium compounds with insulin mimetic properties is important for investigations into the mechanism of action of these complexes. In this work, we report the synthesis of three new compounds related to the (dipicolinato)dioxovanadium(V) complex: (4-hydroxy-2,6-pyridinedicarboxylato)dioxovanadium(V), (diaqua)(4-hydroxy-2,6-pyridinedicarboxylato)oxovanadium(IV) and (4-amino-2,6-pyridinedicarboxylato)dioxovanadium(V), and present the first preliminary kinetic study of a vanadium dipicolinate system. One of these complexes, (4-hydroxy-2,6-pyridinedicarboxylato)oxovanadium(V), is investigated in greater detail with regard to chemistry, structure, kinetics and insulin-like properties in rats with streptozotocin-induced diabetes. Oral administration of [VO 2 (dipic-OH)] − was found to be effective in lowering both the hyperglycemia and hyperlipidemia of diabetes. This is the first report of the effective lowering of diabetic hyperlipidemia by a vanadium(V) coordination complex.

Chloro-substituted dipicolinate vanadium complexes: synthesis, solution, solid-state, and insulin-enhancing properties.

Three vanadium complexes of chlorodipicolinic acid (4-chloro-2,6-dipicolinic acid) in oxidation states III, IV, and V were prepared and their properties characterized across the oxidation states. In addition, the series of hydroxylamido, methylhydroxylamido, dimethylhydroxylamido, and diethylhydroxylamido complexes were prepared from the chlorodipicolinato dioxovanadium(V) complex. The vanadium(V) compounds were characterized in solution by (51)V and (1)H NMR and in the solid-state by X-ray diffraction and (51)V NMR. Density Functional Theory (DFT) calculations were performed to evaluate the experimental parameters and further describes the electronic structure of the complex. The small structural changes that do occur in bond lengths and angles and partial charges on different atoms are minor compared to the charge features that are responsible for the majority of the electric field gradient tensor. The EPR parameters of the vanadium(IV) complex were characterized and compared to the corresponding dipicolinate complex. The chemical properties of the chlorodipicolinate compounds are discussed and correlated with their insulin-enhancing activity in streptozoticin (STZ) induced diabetic Wistar rats. The effect of the chloro-substitution on lowering diabetic hyperglycemia was evaluated and differences were found depending on the compounds oxidation state similar as was observed for the vanadium III, IV and V dipicolinate complexes (P. Buglyo, D.C. Crans, E.M. Nagy, R.L. Lindo, L. Yang, J.J. Smee, W. Jin, L.-H. Chi, M.E. Godzala III, G.R. Willsky, Inorg. Chem. 44 (2005) 5416-5427). However, a linear correlation of oxidation states with efficacy was not observed, which suggests that the differences in mode of action are not simply an issue of redox equivalents. Importantly, our results contrast the previous observation with the vanadium-picolinate complexes, where the halogen substituents increased the insulin-enhancing properties of the complex (T. Takino, H. Yasui, A. Yoshitake, Y. Hamajima, R. Matsushita, J. Takada, H. Sakurai, J. Biol. Inorg. Chem. 6 (2001) 133-142).

Vanadium(IV/V) speciation of pyridine-2,6-dicarboxylic acid and 4-hydroxy-pyridine-2,6-dicarboxylic acid complexes: potentiometry, EPR spectroscopy and comparison across oxidation states

Evaluation of stability of vanadium(IV) and (V) complexes under similar conditions is critical for the interpretation and assessment of bioactivity of various vanadium species. Detailed understanding of the chemical properties of these complexes is necessary to explain differences observed their activity in biological systems. These studies are carried out to link the chemistry of both vanadium(IV) and (V) complexes of two ligands, 2,6-pyridinedicarboxylic acid (dipicolinic acid, H(2)dipic) and 4-hydroxy-2,6-pyridinedicarboxylic acid (H(2)dipic-OH). Solution speciation of the two 2,6-pyridinedicarboxylic acids with vanadium(IV) and vanadium(V) ions was determined by pH-potentiometry at I=0.2 M (KCl) ionic strength and at T=298 K. The stability and the metal affinities of the ligands were compared. Vanadium(V) complexes were found to form only tridentate coordinated 1:1 complexes, while vanadium(IV) formed complexes with both 1:1 and 1:2 stoichiometries. The formation constant reflects hindered coordination of a second ligand molecule, presumably because of the relatively small size of the metal ion. The most probable binding mode of the complexes was further explored using ambient and low temperature EPR spectroscopy for vanadium(IV) and 51V NMR spectroscopy for vanadium(V) systems. Upon complex formation the pyridinol-OH in position 4 deprotonates with pK approximately 3.7-4.1, which is approximately 6 orders of magnitude lower than that of the free ligand. The deprotonation enhances the ligand metal ion affinity compared to the parent ligand dipicolinic acid. In the light of the speciation and stability data of the metal complexes, the efficiency of the two ligands in transporting the metal ion in the two different oxidation states are assessed and discussed.