A new family of insulin-mimetic vanadium complexes derived from 5-carboalkoxypicolinates

The reaction of 5-carboalkoxypicolinic acid (5ROpicH, R=Me, Et, iPr, sBu; 1a-d) with vanadyl sulfate yielded the complexes [VO(H2O)(5R-Opic)(2)] , 2a-d, with H2O and one of the picolinato ligands in the equatorial positions, and the second picolinate occupying equatorial (N) and axial (0) positions. Reaction of la with [NH4][VO3] yielded [NH4][VO2(5MeOpic)(2)], [NH4]-3, in which the N functions of the picolinates are trans to the doubly bonded, cis-positioned oxo groups. Complexes 1a (.) H2O, 1b, 1c, 2a(.)3.5H(2)O and [NH4]-3(.)4H(2)O have been structurally characterised. A detailed pH-potentiometric solution speciation analysis of the system VO2+-1a revealed a dominance of VO(5 OMepic)(2) between pH 2 and 6, with the same coordination pattern, evidenced by EPR spectroscopy, as in the crystalline solid state. In ternary systems containing physiological concentrations of the low molecular mass biogenic binders (B) lactate, oxalate, citrate or phosphate, ternary species of general composition VO(5 MeOpic)B dominate at physiological pH, with citrate being the most effective competitor for picolinate. All of the complexes trigger glucose uptake and degradation by simian virus modified mice fibroblasts at non-toxic concentrations (<100 mum), with 2a, [VO2(pic)(2)](-) and [VO2(dipic)](-) being at least as effective as insulin. Vanadium uptake by the cells is most effective in the case of 2a. 2a also effectively inhibits free fatty acid release by rat adipocytes treated with epinephrine, thus mimicking the inhibition of lipolysis by insulin.