Insulin mimetics

K. Fukui, Y. Fujisawa, H. Ohya-Nishiguchi, H. Kamada and H. Sakurai, In vivo coordination structural changes of a potent insulin-mimetic agent, bis(picolinato)oxovanadium(IV), studied by electron spin-echo modulation spectroscopy, J. Inorg. Biochem., 1999, 77, 215. 

V VO(maltate)2 Type II diabetes BMOV insulin mimetic... 

Examples of Vanadium Compounds Tested as Insulin Mimetic Agents. 

Figure 7.3 Structures of vanadium(IV) insulin mimetic agents. (A) BMOV (B) VO(acac)2 (C) VO(Me-acac)2 (D) VO(Et-acac)2.

Therapy for insulin-dependent diabetes mellitus is usually achieved by daily subcutaneous injections of insulin, and insulin-mimetics which can be orally administered may be useful for the treatment of type I diabetes (insulin dependent) if suitable complexes of low toxicity can be identified (510, 511). 

It was discovered nearly 20 years ago that V(V) as vanadate and V(IV) as vanadyl can mimic some of the effects of insulin (stimulate glucose uptake and oxidation and glycogen synthesis) (512, 513). Vanadate is an effective insulin mimetic in the diabetic rat (514), but has proved to be too toxic for human use. Vanadyl, as VOS04, is also unsuitable because high doses are needed on account of its poor oral absorption. Vanadium complexes with organic ligands have proved to be less toxic and can have improved aqueous solubility and lipophil-icity. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

Fig. 25. X-ray crystal structure of trinuclear complex [Cr30(02CCH2CH3)6(H20)3]+ 107, a potential insulin mimetic. Adapted from (537).

The potentially serious aspects of vanadium pollution, the function of biologically occurring enzyme systems, the role of vanadium on the function of numerous enzymes, and the associated role in the insulin-mimetic vanadium compounds are inextricably linked. The key to our understanding all such functionality relies on understanding the basic chemistry that underlies it. This chemistry is determined to a significant extent by the V(IV) and V(V) oxidation states but clearly is not restricted to these states. Indeed, the redox interplay between the vanadium oxidation states can be a critical aspect of the biological functionality of vanadium, particularly in enzymes such as the vanadium-dependent nitrogenases, where redox reactions are the basis of the enzyme functionality. 

Crans, D.C., L. Yang, T. Jakusch, and T. Kiss. 2000. Aqueous chemistry of ammonium (dipicolinato)oxovanadate(V) The first organic vanadium(V) insulin-mimetic compound. Inorg. Chem. 39 4409 1416. 

Many peroxovanadates have potent insulin-mimetic properties [1,2]. Apparently, this functionality derives from the ability of these compounds to rapidly oxidize the active site thiols found in the group of protein tyrosine phosphatases that are involved in regulating the insulin receptor function [3], The discovery of vanadium-dependent haloperoxidases in marine algae and terrestrial lichens provided an additional stimulus in research toward obtaining functional models of peroxidase activity, and there is great interest in duplicating the function of these enzymes (see Section 10.4.2). 

Because of the asymmetry of hydroxylamines and the fact that they are com-plexed by vanadate in a side-on fashion similar to hydrogen peroxide, they provide details of the chemistry not otherwise easily accessible. Further interest in these compounds arises from both their in vivo and in vitro insulin-mimetic properties. Animal studies have shown that the bis(., ., -dimcthyl)hydroxamidohydroxooxovan-adate is as effective as other insulin-mimetics such as bis(maltolato)oxovana-dium(IV). Unlike the peroxo complexes, the hydroxylamine complexes influence enzyme activity by a nonoxidative mechanism [4,5],... 

Shaver, A., D.A. Hall, J.B. Ng, A.-M. Lebuis, R.C. Hynes, and B.I. Posner. 1995. Bisperoxovanadium compounds Synthesis and reactivity of some insulin mimetic complexes. Inorg. Chim. Acta 229 253-260. 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

Vanadium has effects similar to and different from that of insulin [100,101,124], The antidiabetic influence of the metal can be considered insulin-enhancing, rather than insulin-mimetic, because vanadium compounds cannot totally substitute for insulin in any model of diabetes that strictly requires insulin, such as the BB rat [125], a model of type 1 diabetes. In addition, vanadium can exert its antidiabetic effects via a mechanism or combination of mechanisms distinct from that of insulin. The metabolic actions of vanadium on metabolism do not include all of the actions of insulin, yet normal animals produce less serum insulin when given vanadium. The terms insulin-mimetic or insulin-like frequently appear in the literature for actions of vanadium that cannot be classified as similar to or different from that of insulin in the experimental system utilized. 

The antineoplastic activity of vanadium compounds has been studied for some time. In 1979, the metalocene compound, biscyclopentadienyldichloro-Vanadium(IV), (C5H5)VCI2, was found to have antitumor activity [161], The compound inhibited the growth of various cancer cell lines and the growth of solid tumors in vivo. Vanadium(V) peroxocomplexes with known insulin-mimetic activity were shown to have antitumor activity against murine leukemia cells at that time. Vanadocene compounds are now known to induce apoptosis in cell lines. The apoptotic signal... 

Cam, M.C., R.W. Brownsey, and J.H. McNeill. 2000. Mechanisms of vanadium action Insulin-mimetic or insulin-enhancing agent Can. J. Physiol. Pharmacol. 78 829-847. 

Dubyak, G.R. and A. Kleinzeller. 1980. The insulin-mimetic effects of vanadate in isolated rat adipocytes. Dissociation from effects of vanadate as a (Na+-K+)ATPase inhibitor. The J. Biol. Chem. 255 5306-12. 

Yamaguchi, M., K. Wakasugi, R. Saito, Y. Adachi, Y. Yoshikawa, H. Sakurai, and A. Katoh. 2006. Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-sub-stituted 2(l//)-pyrimidinones and their insulin-mimetic activities. J. Inorg. Biochem. 100 260-9. 

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