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

Abstract

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 VOSO(4) (IC50=1.00 mM) and ZnSO(4) (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 micromol) 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.

Synthesis and Characterization of a Copper(II) Complex with 6-Hydroxypicolinic Acid and 3-Picoline

“…[1][2][3][4][5][6][7] Until now, there are only few reports regarding insulinomimetic properties of picolinate complexes bearing electron-donating groups such as a methyl group. 3,8 Picolinate ligands favor the formation of mononuclear or polynuclear complexes due to their inherent tendency to form a chelate ring. They can also act as bridging ligands (up to four metal ions), 9 thus offering a possibility of using them as building blocks to assemble multi-dimensional frameworks.…”

Anti-diabetes Effect of Zn(II)/Carnitine Complex by Oral Administration.

“…1) We reported that Zn(II) complexes with nicotinamide, maltol, amino acids, picolinic acid, picolinamide, and their derivatives have high insulinomimetic activities in in vitro and in vivo studies. [2][3][4][5][6][7] However, these complexes were effective in showing the lowering effect of blood glucose by daily intraperitonial injections to type 2 diabetes mellitus. When aiming at the clinical use of the complexes, it is essentially important to find complexes that are effective on oral administration.…”

Oral Administration of Bis(aspirinato)zinc(II) Complex Ameliorates Hyperglycemia and Metabolic Syndrome-Like Disorders in Spontaneously Diabetic KK-Ay Mice: Structure-Activity Relationship on Zinc-Salicylate Complexes

“…Since 2000, we have proposed several types of zinc(II) (Zn) complexes with various coordination modes, [4][5][6][7][8] in which Zn complexes with Zn(O 4 ) and Zn(N 2 O 2 ) coordination environments showed anti-diabetic effect on oral administration.…”

“…3) We have developed anti-diabetic metal complexes as new candidates for hypoglycemic agents. Since 2000, we have proposed several types of zinc(II) (Zn) complexes with various coordination modes, [4][5][6][7][8] in which Zn complexes with Zn(O 4 ) and Zn(N 2 O 2 ) coordination environments showed anti-diabetic effect on oral administration. 9) Coincidently, a high dose of salicylates was found to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients.…”

“…[4][5][6]24) These complexes were characterized for physicochemical properties determined by elemental analysis, IR spectrometry, and mass spectrometry. Elemental analyses for C, H, and N were performed by a Perkin-Elmer 240C elemental analyzer (Perkin-Elmer, Tokyo, Japan).…”