Howard Research Interests

Vanadium-Based Anti-Hyperglycemic Drugs

Orally administered, aqueous solutions of simple vanadium salts, such as NaVO3, have been known to lower the glucose levels in the blood of diabetics since 1899.  With the discovery of insulin in 1922 however, interest in using vanadium compounds to treat hyperglycemia was lost, until the 1990’s.  Since that time, a number of vanadium-based insulin mimics have been described in the literature.  Furthermore, insulin mimicry has also been accomplished with compounds of zinc, molybdenum, and tungsten.

The mechanism(s) by which vanadium compounds treat hyperglycemia are not well understood, and many questions persist.  Orally administered vanadium-based drugs enter the digestion system where the pH can be as low as 1.0.  Many vanadium complexes decompose in such an acidic environment, forming inorganic oxovanadium ions like [VO2]+ and [VO]2+, which enter the blood stream.  Some vanadium complexes manage to survive digestion and enter the blood stream intact, but these complexes, like the oxovanadium ions, are quickly bound to the proteins apo-transferrin (apo-Trf) and human serum albumin (HSA) in the blood, or to anions present in the blood such as glycinate, lactate, citrate, bicarbonate, and phosphates.  These blood-based “ligands” decompose the complex by displacing the original ancillary ligands.

Since the original vanadium complex seems unlikely to exist in the blood, one may expect that the vanadium-protein species are actually responsible for insulin mimicry, and that the identity of the original ingested vanadium complex is not significant.  Furthermore, one may also expect that using a vanadium complex with organic ancillary ligands should be no more effective than using simple inorganic vanadium compounds such as NaVO3 or VOSO4.

These expectations are NOT supported by experiment however!  Vanadium complexes with organic ligands such as dipicolinate and maltolate have been found to be more effective insulin mimetics than simple inorganic vanadium compounds such as VOSO4.  Thus, the use of vanadium complexes instead of inorganic vanadium salts does matter, and designing vanadium complexes with optimal insulin-mimicking abilities is important.

We are interested in preparing and fully characterizing stable, water-soluble vanadium complexes with very tightly-bound, ancillary organic ligands.  The stabilities of these complexes in acidic solution (pH = 1) and in the presence of apo-Trf and HSA are examined, and selected compounds are evaluated as insulin mimics.  This research is aimed at addressing the question concerning the importance of complex stability in insulin mimicry.

 

Relevant Publication

"Aqueous Acid-Base Chemistry Involving Dioxovanadium(V) Complexes of 2,6-Pyridinedimethanol, and the X-Ray Structures of Na[VO2{2,6-(OCH2)2NC5H3}] · 4 H2O and [1-H-2,6-(HOCH2)2NC5H3]+Cl-."  Fites, R. J.; Yeager, A. T.; Sarvela, T. L.; Howard, W. A.; Zhu, G.; Pang, K.  Inorg. Chim. Acta 2006, 359, 248-56.

 

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