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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040525-08
Application #
2392061
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1989-04-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Willsky, Gail R; Halvorsen, Katherine; Godzala 3rd, Michael E et al. (2013) Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients. Metallomics 5:1491-502
Willsky, Gail R; Chi, Lai-Har; Godzala 3rd, Michael et al. (2011) Anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes. Coord Chem Rev 255:2258-2269
Crans, Debbie C; Zhang, Boyan; Gaidamauskas, Ernestas et al. (2010) Is vanadate reduced by thiols under biological conditions? Changing the redox potential of V(V)/V(IV) by complexation in aqueous solution. Inorg Chem 49:4245-56
Cohen, Mitchell D; Sisco, Maureen; Prophete, Colette et al. (2010) Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium. Inhal Toxicol 22:169-78
Ooms, Kristopher J; Bolte, Stephanie E; Baruah, Bharat et al. (2009) (51)V solid-state NMR and density functional theory studies of eight-coordinate non-oxo vanadium complexes: oxidized amavadin. Dalton Trans :3262-9
Willsky, G R; Goldfine, A B; Kostyniak, P J et al. (2001) Effect of vanadium(IV) compounds in the treatment of diabetes: in vivo and in vitro studies with vanadyl sulfate and bis(maltolato)oxovandium(IV). J Inorg Biochem 85:33-42