Speciation of potential anti-diabetic vanadium complexes in real serum samples

In this work the speciation in real serum samples of five VIVO complexes with potential application in the therapy of diabetes was studied through EPR spectroscopy as a function of V concentration (45.4, 90.9 and 454.5 ?M) and time (0-180 min). [VO(dhp)2], [VO(ma)2], [VO(acac)2], [VO(pic)2(H2O)], and [VO(mepic)2], where Hdhp indicates 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone, Hma maltol, Hacac acetylacetone, Hpic picolinic acid, and Hmepic 6-methylpicolinic acid, were examined. The distribution of VIVO2+ among the serum bioligands was calculated from the thermodynamic stability constants in the literature and compared with the experimental results. EPR results, which confirm the prediction, depend on the strength of the ligand L and geometry assumed by the bis-chelated species at physiological pH, cis-octahedral or square pyramidal. With dhp, the strongest chelator, the system is dominated by [VO(dhp)2] and/or cis-VO(dhp)2(Protein); with intermediate strength chelators, i.e. maltolate, acetylacetonate and picolinate, by cis-VO(ma)2(Protein), [VO(acac)2] or [VO(pic)(citrH-1)]3 -/[VO(pic)(lactH-1)]- (citr = citrate and lact = lactate) when the V concentration overcomes 100-200 ?M and by (VO)(hTf)/(VO)2(hTf) when concentration is lower than 100 ?M; with the weakest chelator, 6-methylpicolinate, (VO)(hTf)/(VO)2(hTf), (VO)(HSA) (hTf = human serum transferrin and HSA = human serum albumin), and VO(mepic)(Protein)(OH) are the major species at concentration higher than 100-200 ?M, whereas hydrolytic processes are observed for lower concentrations. For [VO(dhp)2], [VO(ma)2], [VO(acac)2] and [VO(pic)2(H2O)], the EPR spectra remain unaltered with elapsing time, while for mepic they change significantly because the hydrolyzed VIVO species are complexed by the serum bioligands, in particular by lactate. The rate of oxidation in the serum is [VO(dhp)2] > [VO(ma)2] > [VO(acac)2] and reflects the order of E1/2 values.