Vanadium, Copper and Zinc in Medicine

Abstract

The first report of the use of vanadium for the treatment of diabetes mellitus (DM) was published by the French physician Dr. B. Lyonnet, who in 1899 described the ability of the simple vanadium compound sodium vanadate, Na 3 VO 4 (Figure 7.1), to lower the blood sugar levels of diabetic patients [1]. More than 80 years later, both vanadate and the related ion, vanadyl, VO 2þ (Figure 7.1), were shown to exhibit insulin-mimetic effects on the oxidation of glucose in adipocytes (fat cells) of rats [2][3][4], and sodium vanadate was found to be effective in controlling blood glucose levels and reducing cardiac decline in diabetic rats [5]. These early reports led to the synthesis and study of a large number of vanadium-based insulin-mimetic agents, a few of which are shown in Figure 7.1 [6][7][8][9][10][11][12][13][14]. One of these compounds, bis(ethylmaltolato)oxovanadium(IV), BEOV, is currently in phase II clinical trials in the United States as a potential new insulin-mimetic agent for treating diabetes.Vanadium, element 23, is found in low concentrations in the body ($100 mg total) and its function is not known. While vanadium has many oxidation states, those commonly found in the biological system and incorporated into vanadium complexes for treating diabetes are V þ5 , which has the electronic configuration [Ar]3d 0 , and V þ4 , with the configuration [Ar]3d 1 . The formula for vanadate ion is VO 4 À3 , but since the pK a s for the first and second protonation of the ion are $13 and $8 respectively, at neutral pH in dilute solution the ion exists mainly in its diprotonated form, [H 2 VO 4 ] À (Figure 7.1). Since vanadate is isostructural and isoelectronic with phosphate but cannot undergo the same chemical reactions as phosohate, vanadate is often used as an inhibitor in mechanistic studies of biochemical reactions that require phosphate. Like phosphate, vanadate can also form higher-order structures, but vanadate has a stronger tendency to nucleate and can form species that contain up to 10 vanadium ions, such as decavanadate, [V 10 O 28 ] 6À [15].The simplest ion in water at neutral pH for aquated V þ4 is [VO(OH)(H 2 O) 4 ] þ , which since it contains a VO 2þ species is often referred to simply as vanadyl. This octahedral complex contains an oxo ligand (O 2À ), a hydroxo group (OH À ) and four bound water molecules. Depending on the concentration of vanadium and the pH of the medium, vanadyl can also form higher-order multinuclear structures in solution. The water exchange rate constant for [VO(OH)(H 2 O) 4 ] þ at 25 C is k $ 5 Â 10 2 s À1 (Figure 1.20) [16].Complexes containing V þ5 are diamagnetic (S ¼ 0). Since the main isotope, 51 V, is NMR 'active' (I ¼ 7/2) and has high natural abundance (>99%), compounds containing V þ5 can easily be studied using NMR. Mononuclear vanadyl complexes are paramagnetic with one unpaired electron -that is, S ¼ 1 / 2 -and, although Metals in MedicineJames C. Dabrowiak not studied with NMR, they can be investigated using electron paramagnetic resonance (EPR) see (Box 7.1). ...