Development of new insulinomimetic zinc(II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies

Three zinc(II) complexes of picolinic acid and its derivatives with a Zn(N2O2) coordination mode were prepared and evaluated for their insulinomimetic activities by in vitro and in vivo studies. By introducing an electron-donating methyl group into the picolinate ligand (pic), bis(6- or 3-methylpicolinato)zinc(II) complexes [Zn(6-mpa)(2) or Zn(3-mpa)(2), respectively] were prepared. The Zn(6-mpa)(2) complex was crystallized as a water adduct [Zn(6-mpa)(2)(H2O)].H2O, in which two carboxylate oxygens and two pyridine nitrogens of 6-mpa and a water oxygen coordinate to a zinc(II) with a trigonal bipyramidal geometry. By in vitro evaluation of the inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, the insulinomimetic activities of Zn(pic)(2), Zn(6-mpa)(2), and Zn(3-mpa)(2) (IC50=0.64+/-0.13, 0.31+/-0.05, and 0.40+/-0.07 mM, respectively) were found to be higher than those of VOSO4 (IC50 =1.00 mM) and ZnSO4 (IC50=1.58+/-0.05 mM) in terms of IC50 value, the 50% inhibition concentrations for the FFA release from the adipocytes. Then, Zn(6-mpa)(2), which exhibited the highest in vitro insulinomimetic activity among three complexes examined., was given at a dose of 3.0 mg (45.9 mu mol) Zn/kg body weight to KK-A(y) mice with type 2 diabetes mellitus by daily intraperitoneal injections for 14 days and it was found that the hereditary high blood glucose levels were lowered during the administration of the complex. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.