Transport of the anti-diabetic VO2+ complexes formed by pyrone derivatives in the blood serum

The biotransformation in the blood serum of the two anti-diabetic agents [VO(ema)2] – or BEOV – and [VO(koj)2] formed by ethylmaltol (Hema) and kojic acid (Hkoj) was studied with EPR spectroscopy, pH-potentiometry and DFT calculations. For comparison, the behavior of the systems with tropolone (Htrop) was also analyzed. The interaction of [VO(ema)2] and [VO(koj)2] with the most important bioligands of the serum, lactic (Hlact) and citric acid (H3citr), human serum transferrin (hTf), human serum albumin (HSA) and immunoglobulin G (IgG) was examined and discussed. Among the several mixed species observed, cis-VO(carrier)2(hTf), cis-VO(carrier)2(HSA) and cis-VO(carrier)2(IgG), where carrier is ethylmaltolate or kojate, with a His-N of the protein coordinated in the equatorial position, are plausible candidates for the transport processes of the drug toward the target organs. The values of the logβ are in the range 19.6–19.8 for the species formed by ethylmaltol and 17.4–17.6 for those formed by kojic acid. The formation of such species was confirmed through pH-titrations of the model systems VO2 +/carrier/1-MeIm and VO2 +/carrier/Ac-his, where 1-MeIm and Ac-his are 1-methylimidazole and N-acetylhistamine, and DFT calculations of 51V Az of the model species cis-[VO(carrier)2(1-MeIm)] and cis-[VO(carrier)2(Ac-his)]. The values of the stability constants for the mixed species observed were used to predict the biodistribution of VO2 + ion between the blood serum components for concentrations of 1, 10 and 50 μM.