Coordination chemistry of vanadium in metallopharmaceutical candidate compounds

The number of patients suffering from diabetes mellitus (DM), which is a chronic metabolic disorder and mainly classified as either insulin-dependent type 1 or non-insulin-dependent type 2, is increasing throughout the world. The sequence of DM progression makes this disease a major health risk in regard to microvascular disease that leads to kidney failure, blindness, and nerve damage as well as macrovascular disease that leads to amputations, cardiovascular disease, and stroke. To treat DM, several types of insulin preparations and synthetic drugs for type 1 and type 2 DM, respectively, are in clinical use. However, there are several problems concerning the insulin preparations and synthetic drugs, such as physical and mental pain due to daily insulin injections and defects involving several side effects, respectively. Thus, the disease demands extraordinary effects to define pathobiochemical pathways and strategies for prevention and to find new therapeutic approaches. For this purpose, oxovanadium(IV) (vanadyl, VO 2+ ) and zinc(II) containing complexes have been explored as treatments for both types of DM. This article reviews the current state of research on insulin-mimetic and antidiabetic metal complexes, with special focus on paramagnetic vanadyl and diamagnetic zinc(II) complexes with different coordination modes, together with possible reaction mechanisms. New drug delivery systems involving enteric-coated capsulation and a biopolymer are also reviewed.

Chemistry and Biochemistry of Insulin-Mimetic Vanadium and Zinc Complexes. Trial for Treatment of Diabetes Mellitus

In order to estimate the impact of the low molecular mass (l.m.m.) VO(IV) binders of blood serum on the potentially insulin-enhancing drug [VO(DHP)2] [DHP = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone], the speciation in the binary system VO(IV)–DHP and in the ternary systems VO–DHP–ligand B (B = oxalate, lactate, citrate or phosphate) was studied by pH-potentiometry at 25.0 °C and at an ionic strength I
= 0.2 mol dm−3 (KCl). The binding modes of the complexes formed were determined by spectroscopic (electronic absorption and EPR) techniques. DHP was found to form stable mono and bis complexes via the coordination of (O,O) chelate(s). Through displacement of the oxo group of VO(IV), the tris complex is also formed, especially at a high excess of ligand. The results in the ternary systems demonstrate that, at physiological pH, none of the B ligands can
compete with DHP; [VO(DHP)2] therefore seems to remain almost completely intact, even in the presence of citrate, the strongest competitor among these B ligands. These findings indicate that, for DHP, unlike maltol or picolinic acid, ternary complex formation and thus transformation reactions with the l.m.m. binders of biofluids, is almost negligible. From among the three carrier molecules, only DHP can efficiently compete with serum transferrin for binding of VO(IV).

Interaction between the low molecular mass components of blood serum and the VO(IV)–DHP system (DHP = 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone)

Aqueous solution studies regarding the identification and characterization of complexes formed by the VIVO ion and 11 3-hydroxy-4-pyridinone derivatives have been performed using EPR and UV/vis spectroscopic techniques. For the three ligands (HL) adequately soluble in water (1-methyl-3-hydroxy-4-pyridinone, 1-methyl-2-ethyl-3-hydroxy-4-pyridinone, and 1,2-diethyl-3-hydroxy-4-pyridinone), potentiometric titrations were performed; the results are consistent with the formation of [V(IV)OL]+, [V(IV)OL2], [V(IV)OL2H(-1)]-, [(V(IV)O)2L2H(-2)], and [V(IV)L3]+ species. Bis chelated complexes are characterized by a cis-trans isomerism, the trans isomer being strongly favored with respect to the cis arrangement. Tris chelated non-oxo V(IV) species were prepared in CH3COOH; their spectroscopic features point to a d(z2) ground state and a geometry intermediate between an octahedron and a trigonal prism, related to the steric requirements of the substituent on the carbon atom in position 2 of the pyridinone ring. Four new solid derivatives, [V(IV)O(1,2-diethyl-3-hydroxy-4-pyridinonato)2], [V(IV)O(1-(p-tolyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], [V(IV)O(1-(p-(n-butyl)phenyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], and [V(IV)O(1-(p-(n-hexyl)phenyl)-2-ethyl-3-hydroxy-4-pyridinonato)2], were isolated and characterized; they exhibited a five-coordinate geometry close to square-pyramid. A criterion for establishing the degree of distortion toward the trigonal-bipyramid on the basis of the electronic absorption spectra is provided. Relationships between the pKa of the -OH group in position 3 of the ring and (i) log K of mono and bis chelated complexes, (ii) pK of the water molecule in cis-[V(IV)OL2(H2O)], (iii) log K of tris chelated species [V(IV)L3]+, and (iv) 51V hyperfine coupling constant (Az) have been established and discussed for a number of pyrone, pyridinone, and catechol ligands. The results are rationalized by assuming for pyridinones an electronic structure intermediate between that of pyrones and catechols. The relationships are valuable to the understanding of the behavior of VIVO species in aqueous solution.

Spectroscopic and potentiometric characterization of oxovanadium(IV) complexes formed by 3-hydroxy-4-pyridinones. Rationalization of the influence of basicity and electronic structure of the ligand on the properties of V(IV)O species in aqueous solution.

Celeste Oliveira

Papers

Synthesis and characterization of 3-hydroxy-4pyridinone-oxovanadium(IV) complexes

Characterization of the photolysis products of sec-butylcobaloximes with imidazole and benzimidazole bases