Effects of Decavanadate Salts with Organic and Inorganic Cations on Escherichia coli, Giardia intestinalis, and Vero Cells.

Decavanadate salts with nicotinamide (3-pyridinecarboxamide, 3-pca) and isonicotinamide (4-pyridinecarboxamide, 4-pca) in both neutral and protonated forms, (3-Hpca)4[H2V10O28]·2H2O·2(3-pca) (complex I) and (4-Hpca)4[H2V10O28]·2(4-pca) (complex II), have been synthesized and characterized by vibrational spectroscopy (infrared and Raman), thermogravimetric analysis (TGA), 51V NMR, and single-crystal X-ray diffraction analysis. The effects of sodium decavanadate (henceforth called NaV10) and compounds I and II on Escherichia coli, Giardia intestinalis, and Vero (African green monkey epithelial kidney) cells were evaluated. Enhanced growth inhibitory activity against E. coli cultures was observed upon treatment with products I and II when compared to that with NaV10 (GI50 values of 2.8, 4.0, and 11 mmol L-1, respectively), as well as lower cell viability as measured by the intake of propidium iodide (PI). Exposure of Giardia trophozoites to NaV10 and II revealed reduction in trophozoite viability (GI50 values of ca. 10 µmol L-1) and affected the parasite adherence to both polystyrene culture tubes and a monolayer of Vero cells, even at low concentrations. A lesser effect on Giardia was shown for I. Furthermore, all three compounds were significantly less toxic to Vero cells than the reference drug, albendazole, employed in the treatment of giardiasis. Toxicity reports of oxidovanadium compounds toward Giardia are unprecedented and open a path to the development of new therapeutic agents.

A new approach to study semi-coordination using two 2-methyl-5-nitroimidazole copper(ii) complexes of biological interest as a model system.

Two novel copper(ii) complexes [Cu(2mni)2(H2O)2](NO3)2·2H2O (1) and [Cu(2mni)2(NO3)2] (2), where 2mni is 2-methyl-5-nitroimidazole, were prepared and characterized in the solid state using single-crystal and powder X-ray diffraction analyses, EPR, electronic and vibrational spectroscopies (FTIR and Raman), and thermogravimetric methods. Both products present an elongated distorted octahedral geometry with axial Cu-O bond lengths of 2.606(14) and 2.593(15) Å, indicating semi-coordination. Density functional theory (DFT) calculations at the B3LYP/LANL2DZ theory level were used to study the electronic properties of 1 and 2. The Independent Gradient Model (IGM) was employed to determine the Intrinsic Bond Strength Index (IBSI) of the semi-coordination and to plot δg isosurfaces for the electronic sharing between the metal center and ligands. A moderate to weak antibacterial activity against Escherichia coli cultures was found for 1 with a 50% growth inhibition (GI50) value of 0.25 mmol L-1. To the best of our knowledge, this is the first time that the semi-coordination analysis using IGM was carried out for a copper(ii) complex with axial elongation, finding a good correlation between the bond length and the IBSI, and the study was extended for a series of analogous complexes described in the literature.

The antihyperglycemic and hypolipidemic activities of a sulfur-oxidovanadium(IV) complex.

This study describes the synthesis, characterization, and biological activity of a new class of antidiabetic oxidovanadium(IV)-complexes with S2O2 coordination mode. The target complex 3,6-dithio-1,8-octanediolatooxidovanadium(IV), abbreviated as ([VIVO(octd)]), where octd = 3,6-dithio-1,8-octanediol, is formed from the reaction between the 3,6-dithio-1,8-octanediol and vanadyl sulfate (VIVOSO4). The effects of treatment with ([VIVO(octd)] on blood glucose, lipidic profile, body weight, food intake, water intake, urinary volume, glycogen levels, and biomarkers for liver toxicity were investigated using a streptozotocin (STZ)-induced diabetic Wistar rats model. The results have shown that the [VIVO(octd)] complex caused a significant decrease in blood glucose (247.6 ± 19.3 mg/dL vs 430.1 ± 37.6 mg/dL diabetic group, p < 0.05), triglycerides (TG, 50%) and very low-density cholesterol (VLDL-C, 50%) levels in STZ-diabetic rats after 3 weeks of treatment. The [VIVO(octd)] has shown antihyperglycemic activity in diabetic rats as well as a reduction in elevated lipid levels. Time-dependent studies using EPR and 51V NMR spectroscopy of [VIVO(octd)] were done in aqueous solutions to determine the complex stability and species present in the oral gavage solution used for complex administration. The spectroscopic studies have shown that the antidiabetic/hypolipidemic activity could be attributed to [VIVO(octd)], vanadium species resulting from redox processes, the hydrolysis of [VIVO(octd)] and its decomposition products, or some combination of these factors. In summary, the oxidovanadium(IV) complex containing the S2O2 donor ligand has desirable antidiabetic properties eliminating the symptoms of Diabetes mellitus and its comorbidities.

In Vitro, Oral Acute, and Repeated 28-Day Oral Dose Toxicity of a Mixed-Valence Polyoxovanadate Cluster.

Polyoxovanadates (POV) are a subgroup of polyoxometalates (POM), which are nanosized clusters with reported biological activities. This manuscript describes the first toxicity evaluation of a mixed-valence polyoxovanadate, pentadecavanadate, (Me4N)6[V15O36Cl], abbreviated as V15. Cytotoxicity experiments using peripheral blood mononuclear cells (PBMC), larvae of Artemia salina Leach, and in vivo oral acute and repeated 28-day doses in mice was carried out. The LC50 values in PBMC cells and A. salina were 17.5 ± 5.8 µmol L-1, and 17.9 µg L-1, respectively, which indicates high cytotoxic activity. The toxicity in mice was not observed upon acute exposure in a single dose, however, the V15 repeated 28-day oral administration demonstrated high toxicity using 25 mg/kg, 50 mg/kg and, 300 mg/kg doses. The biochemical and hematological analyses during the 28-day administration of V15 showed significant alteration of the metabolic parameters related to the kidney and liver, suggesting moderate toxicity. The V15 toxicity was attributed to the oxidative stress and lipid peroxidation, once thiobarbituric acid (TBAR) levels significantly increased in both males and females treated with high doses of the POV and also in males treated with a lower dose of the POV. This is the first study reporting a treatment-related mortality in animals acutely administrated with a mixed-valence POV, contrasting with the well-known, less toxic decavanadate. These results document the toxicity of this mixed-valence POV, which may not be suitable for biomedical applications.

Polyoxovanadates as new P-glycoprotein inhibitors: insights into the mechanism of inhibition.

A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V10 O28 ]6- (V10 ), [H6 V14 O38 (PO4 )]5- (V14 ), [V15 O36 Cl]6- (V15 ) and [V18 O42 I]7- (V18 ) as inhibitors of three major multidrug resistance-linked ABC transporters: P-glycoprotein (P-gp), ABCG2 and MRP1. All of the POVs selectively inhibited P-gp. V10 and V18 were the two most promising compounds, with IC50 values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC50 value of 1.26 µm. V10 and V18 triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V10 with rhodamine B, RhoB-V10 . The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand-binding site, opening new possibilities in the development of potent modulators of ABC transporters.

PtIV- or MoVI-substituted decavanadates inhibit the growth of Mycobacterium smegmatis.

Inhibitory effects of two monosubstituted decavanadates by PtIV in monoplatino(IV)nonavanadate(V) ([H2PtIVV9O28]5-, V9Pt), and by MoIV in monomolybdo(VI)nonavanadate(V) ([MoVIV9O28]5-,V9Mo) were investigated against the growth of Mycobacterium smegmatis with the EC50 values of 0.0048 mM and 0.015 mM, respectively. These compare to the reported inhibitory value for decavanadate ([V10O28]6-/[HV10O28]5-, V10) on Mycobacterium smegmatis (EC50 = 0.0037 mM). Time-dependent 51V NMR spectroscopic studies were carried out for all three polyanions in aqueous solution, biological medium (7H9), heated and non-heated supernatant to evaluate their stability in their respective media, monitor their hydrolysis to form various oxovanadates over time and calculate the EC50 values. These studies allow us to calculate adjusted and maximum EC50 for the polyoxovanadate (POV) present in solution at the beginning of the study when there is most intact anion in the media and thus the EC50 values represent the initial effects of the POVs. The results have shown that V10 is 1.3 times more potent than V9Pt and 4 times more potent than V9Mo, indicating that the inhibitory effects of monosubstituted polyanions are related to the V10 structure. We attributed the minor differences in the growth inhibitory effects to the differences in charges (5- vs 6-) of V9Pt and V9Mo compared to V10 and/or the differences in the chemical composition. We concluded that the potency of the growth inhibition by V10 is mainly due to the chemical properties of the vanadium and the decametalate's unique structure even though the presence of the Mycobacterium smegmatis facilitate hydrolysis of the anions. SYNOPSIS: Two decavanadate derivatives, monoplatino(IV)nonavanadate(V) ([H2PtIVV9O28]5-), monomolybdo(VI)nonavanadate(V) ([MoVIV9O28]5-) and decavanadate are more potent growth inhibitors of Mycobacterium smegmatis than monomeric vanadate. The spectroscopic characterization carried out in the growth medium led to the conclusion that both the decavanadate structure and its properties are important for its growth effects.

Stability in solution and chemoprotection by octadecavanadates(IV/V) in E. coli cultures.

Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.

Vanadium(IV)-diamine complex with hypoglycemic activity and a reduction in testicular atrophy.

The insulin enhancing activity, histological analysis and, testicular degeneration by a VIVO-complex containing the 2,2'-(ethane-1,2-diylbis(azanediyl))diethanolate ligand, VOIV(C6H14N2O2-κ2N,κ2O), abbreviated VIVO(BHED), were investigated in diabetic male Wistar rats. The complex was administered by oral gavage of freshly prepared solutions of vanadium complex. Biological studies demonstrated that the vanadium complex normalized the elevated glucose levels in male Wistar rats with streptozotocin-induced diabetes and these compounds also avoided common responses in diabetic animals such as weight loss and reduction in the size of the epididymis, prostate, testis and seminal gland. The 51V NMR and EPR studies showed the formation of VIVO(BHED) and the oxidation product [VVO2BHED]- with two possible decomposition pathways. In summary, these studies demonstrate that the VIVO(BHED) complex or its decomposition products show similar effects as insulin in decreasing elevated blood glucose levels.

Polyoxometalates function as indirect activators of a G protein-coupled receptor.

The luteinizing hormone receptor (LHR), a G protein-coupled receptor (GPCRs), can initiate signaling in the presence of some vanadium-containing compounds as a result of vanadium compound interactions with the membrane lipids and/or the cell membrane lipid interface. The ability of LHR expressed in CHO cells to initiate signaling in the presence of highly charged and water-soluble polyoxovanadates (POV) including Na3[H3V10O28] (V10) and two mixed-valence heteropolyoxovanadates, K(NH4)4[H6V14O38(PO4)]·11H2O (V14) and [(CH3)4N]6[V15O36(Cl)] (V15), was investigated here. Interactions of the vanadium compounds with CHO cells decreased the packing of membrane lipids, drove aggregation of LHR and increased signal transduction by LHR. Cell responses were comparable to, or in the case of V14 and V15, greater than those seen for cells treated with human chorionic gonadotropin (hCG), a naturally-occurring LHR ligand produced in early pregnancy in humans. POV effects were observed for CHO cells where LHR was expressed at 10 000 or 32 000 LHR per cell but not when LHR was overexpressed with receptor numbers >100 000 LHR per cell. To determine which POV species were present in the cell medium during cell studies, the speciation of vanadate (V1), V10, V14 or V15 in cell medium was monitored using 51V NMR and EPR spectroscopies. We found that all the POVs initiated signaling, but V15 and V10 had the greatest effects on cell function, while V1 was significantly less active. However, because of the complex nature of vanadium compounds speciation, the effects on cell function may be due to vanadium species formed in the cell medium over time.