The complexation of (VO2+)-O-IV ion with 10 picolinate and quinolinate derivatives, provided with the donor set (N, COO-), was studied in aqueous solution and in the solid state through the combined application of potentiometric (pH-titrations), spectroscopic (EPR, UV/vis and IR spectroscopy), and computational (density functional theory (DFT) calculations) methods. Such derivatives, that form potent insulin-enhancing (VO2+)-O-IV compounds, are picolinic (picH), 6-methylpicolinic (6-mepicH), 3-methylpicolinic (3-mepicH), 5-butylpicolinic or fusaric (fusarH), 6-methyl-2,3-pyridindicarboxylic (6-me-2,3-pdcH(2)), 2-pyridylacetic (2-pyacH), 2-quinolinecarboxylic or quinaldic (quinH), 4-hydroxyquinoline-2-carboxylic or kynurenic (kynurH), 1-isoquinolinecarboxylic (1-iqcH) and 3-isoquinolinecarboxylic (3-iqcH) acid. On the basis of the potentiometric, spectroscopic, and DFT results, they were divided into the classes A, B, and C. The ligands belonging to class A (3-mepicH, 1-iqcH, 2-pyacH) form square pyramidal complexes in aqueous solution and in the solid state, and those belonging to class B (picH, fusarH, 3-iqcH) form cis-octahedral species, in which the two ligands adopt an (equatorial-equatorial) and an (equatorial-axial) arrangement and one water molecule occupies an equatorial site in cis position with respect to the V=O bond. Class C ligands (6-mepicH, 6-me-2,3-pdcH(2), quinH, kynurH) yield bis chelated species, that in water are in equilibrium between the square pyramidal and trans-octahedral form, where both the ligand molecules adopt an (equatorial-equatorial) arrangement and one water is in trans position with respect to the V=O group. The trans-octahedral compounds are characterized by an anomalous electron paramagnetic resonance (EPR) response, with A(z) value being reduced by about 10% with respect to the prediction of the "additivity rule". DFT methods allow to calculate the structure, V-51 hyperfine coupling constant (A(z)), the stretching frequency of V=O bond (nu(V=O)), the relative stability in aqueous solution, and the electronic structure and molecular orbital composition of bis chelated complexes. The results were used to explain the biotransformation of these potent insulin-enhancing compounds in blood serum.