Inhibitory effects of decavanadate on several enzymes and Leishmania tarentolae in vitro.

Multiple studies report apparent effects of vanadium on various systems in vivo and in vitro. Vanadium species may be possible deterrents for the growth of the Leishmania parasite, which causes the sometimes deadly diseases known as leishmaniasis. The current studies focus specifically on decavanadate V(10)O(28)(6-) (V10), which has a potential to be a potent effector for disease treatment. The X-ray structure of a new solvate salt of V10, namely (NH(4))(6)V(10)O(28)·5H(2)O, is also reported. Other vanadium complexes with imidazole carboxylate, anthranilate, or picolinate were also evaluated. The yellow-orange oxoanion, used as the (NH(4))(6)V(10)O(28)·6H(2)O salt, was tested (at 1-100 µM) directly with two strains of Leishmania tarentolae promastigotes in culture to evaluate the effect on cell viability. Vanadium coordination complexes are known effective inhibitors of phosphatases. Using the artificial phosphatase substrate para-nitrophenylphosphate in the presence of a bovine calf intestine alkaline phosphatase enzyme, V10 (from 5 to 100 µM) was shown to be a mixed inhibitor for this enzyme and decreased the activity of the other two phosphatases tested. The effect of V10 and the other vanadium complexes on the activity of phosphoglycerate mutase B (PGAM), an important enzyme in glycolysis and gluconeogenesis, was also evaluated. At 10 µM, V10 was the most potent inhibitor of PGAM, with an apparent reduction of about 50%. Taken together, we speculate that V10 could have a role in treating Leishmania diseases.

New application for expanded porphyrins: sapphyrin and heterosapphyrins as inhibitors of Leishmania parasites.

Sapphyrins and a series of related porphyrinoid macrocycles have been investigated as potential agents for the treatment of leishmaniasis. The effectiveness of the compounds was evaluated in vitro upon incubation with Leishmania tarentolae or L. panamensis amastigotes and promastigotes. Their effectiveness was also assessed against intracellular L. panamensis. The cytotoxicity of the compounds was evaluated in vitro using the U937 human promonocyte cell line. Effectiveness and cytotoxicity were assessed in the presence and absence of visible light to assess the photodynamic activity of the compounds. Sapphyrin and two related heterosapphyrins were shown to be particularly effective as inhibitors of Leishmania. A photodynamic effect was observed, which may be attributed to the formation of reactive oxygen species. Yields of singlet oxygen ((1)O(2)) produced were determined in ethanol solutions by direct measurement of (1)O(2) phosphorescence. Confocal microscopy demonstrated that sapphyrin and related macrocycles were taken up by the Leishmania cells and that their presence induces the formation of mitochondrial superoxide. Sapphyrins have been widely investigated as anticancer agents and we here show activity against the Leishmania parasites.

Inhibition of acid, alkaline, and tyrosine (PTP1B) phosphatases by novel vanadium complexes.

In the course of our investigations of vanadium-containing complexes for use as insulin-enhancing agents, we have generated a series of novel vanadium coordination complexes with bidentate ligands. Specifically we have focused on two ligands: anthranilate (anc(-)), a natural metabolite of tryptophan, and imidizole-4-carboxylate (imc(-)), meant to mimic naturally occurring N-donor ligands. For each ligand, we have generated a series of complexes containing the V(III), V(IV), and V(V) oxidation states. Each complex was investigated using phosphatase inhibition studies of three different phosphatases (acid, alkaline, and tyrosine (PTP1B) phosphatase) as prima facia evidence for potential use as an insulin-enhancing agent. Using p-nitrophenyl phosphate as an artificial phosphatase substrate, the levels of inhibition were determined by measuring the absorbance of the product at 405nm using UV/vis spectroscopy. Under our experimental conditions, for instance, V(imc)(3) appears to be as potent an inhibitor of alkaline phosphatase as sodium orthovanadate when comparing the K(cat)/K(m) term. VO(anc)(2) is as potent an inhibitor of acid phosphatase and tyrosine phosphatase as the Na(3)VO(4). Thus, use of these complexes can increase our mechanistic understanding of the effects of vanadium in vivo.