Vanadate and other vanadium compounds are currently being evaluated in humans as oral insulin mimetic drugs. The complex chemistry of vanadate and vanadium compounds has delayed the development of these drugs in part because of toxicity and in part because of the difficulty in determining which compound is the active species. The most commonly proposed mechanism for vanadate-induced insulin mimetic action involves a vanadate ester in a protein tyrosine phosphatase complex. Despite the in vivo formation of vanadate esters upon administration of vanadate or other labile vanadium compounds, little is known about the activities of vanadate esters in biological systems. Such studies have been hampered by the current inadequate information concerning structure, formation and reactivity of vanadate esters. This proposal explores the fundamental chemistry of vanadate under physiological conditions to determine what types of complexes form and how these compounds interact with proteins. Accordingly, these studies are of direct relevance to understanding the insulin mimetic properties of vanadate and other vanadium compounds currently being tested in humans. The four specific aims we will address are: l. To determine the lability of vanadium(+5) complexes of polydentate ligands. 2. To prepare and characterize simple oxovanadium(+5) alkoxides and other model complexes of multidentate ligands. 3. To examine the mechanism and dynamics of oxovanadate's self-exchange and complexation with simple organic ligands. 4. To examine the substrate, cofactor and inhibitor specificity of vanadate esters. The studies described in Specific Aim l will examine the lability of known compounds and develop new compounds that are, or could be, used as potential insulin mimetic agents.
Specific Aims 2 and 3 will characterize the kinds of compounds that can form under physiological conditions.
Specific Aim 4 will determine if these compounds are enzyme substrates, cofactors or inhibitors. The chemical and biochemical studies are closely linked in this project, the former being necessary to define the systems in which vanadium will act as a ground-state (substrate and cofactor) or as a transition-state analog (inhibitor) of phosphate esters. Such information is essential to evaluate mechanisms contributing to vanadate- induced insulin-mimetic action.
