New Insulinomimetic Zinc(II) Complexes of .ALPHA.-Amino Acids and Their Derivatives with Zn(N2O2) Coordination Mode.

Abstract

Key words zinc(II) complex; amino acid; insulinomimetic activity; NIDDM; blood glucose normalizing effect; glucose tolerance test Zinc(II) ion is known to be one of the important essential trace elements found in biological systems and also in many metalloproteins and metalloenzymes which exist in living organisms. Physico-chemical properties of a zinc(II) ion, which functions as a Lewis acid, is entirely unlike those of vanadium ions with a redox property and insulinomimetic activity. Among many pharmacological and nutritional roles of zinc(II) ion, 1) an interesting pharmacological role was reported in 1980, in which a zinc(II) ion acts as an insulinomimics.2) The administration of ZnCl 2 to streptozotocininduced diabetes rats (STZ rats) or ob/ob mice normalized their high blood glucose levels, 3,4) when a high dose 3) and a long-term (8 weeks) administration were given. 4) However, the insulinomimetic activities of zinc(II) complexes have not yet been studied. Thus, we have tried to develop insulinomimetic zinc(II) complexes with various coordination modes around a zinc(II) ion, because zinc(II) ion is generally less toxic than vanadium ions. 5) During our investigation, we found first that zinc(II) maltolate complex with a Zn(O 4 ) coordination mode exibits high insulin-like activities in in vitro.6) On the basis of the results, we examined the structureactivity relationship of Zn(II) complexes, and found that zinc(II) complexes with Zn(N 2 O 2 ) coordination mode exibit higher insulinomimetic activity than those of ZnSO 4 and VOSO 4 . In this paper, we report the insulinomimic zinc(II) complexes with naturally occurring amino acids and their derivatives.The Zn(II) complexes used in this study were readily prepared by adding ZnSO 4 · 7H 2 O to an aqueous solution of lithium or barium salt of the appropriate ligand (generated in situ from ligands and lithium or barium hydroxide) at room temperature. The choice of lithium or barium as cation was made based upon the aqueous solubility of the desired complex. Lithium was preferred instead of barium, because the complex is prone to coprecipitate with barium sulfate in the reaction. All complexes were purified from hot water by recrystallization, identified by the elemental analyses and IR and 1 H-NMR spectra, and found to be molecular complexes without a counter ion.The insulinomimetic activities of the complexes were evaluated by using the isolated rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. 7)The inhibitory effects of the complexes were compared with those of ZnSO 4 and VOSO 4 as positive control. It was revealed that zinc(II) complexes with lower over-all stability constants (log b) than 10.5 exhibited higher insulinomimetic activities than those of ZnSO 4 and VOSO 4 or were comparable to them except Zn(GtG) (IC 50 ϭ3.18) ( Table 1). On the other hand, zinc(II) complexes with His, GeG, and mGeGm (log bϭ12.05, 11.22, and 11.83, respectively) with higher log b values than 11.0 showed essentially no insulinomimet...

Insulinomimetic Zn(II) Complexes as Evaluated by Both Glucose-Uptake Activity and Inhibition of Free Fatty Acids Release in Isolated Rat Adipocytes

“…9,10) The Zn(II) complexes were purified with hot water to obtain bis(thiophene-2-carboxylato)zinc (Zn(tc) 2 ), with 2-propanol to obtain bis(a-furoic acidato)zinc (Zn(fa) 2 ), and with methyl alcohol to obtain bis(thiophene-2-acetato)zinc (Zn(ta) 2 ) and bis(pyrrole-2-carboxylato)zinc (Zn(pc) 2 ).…”

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.…”

Chemistry and Biochemistry of Insulin-Mimetic Vanadium and Zinc Complexes. Trial for Treatment of Diabetes Mellitus

“…Among the wide variety of zinc(II)-amino acids or -peptides complexes prepared, [Zn(thr) 2 ] complex 14 showed the functions, such as blood glucose lowering effect and HbA 1c normalizing effect, suggesting that it is a clinically useful agent to treat type 2 diabetes.…”