A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)2, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)2 as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)2 and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)2, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)2-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)2 and Zn(ma)2 were then compared, and both complexes were found to normalize hyperglycemia in KK-Ay mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)2 improved glucose tolerance in KK-Ay mice much more than did Zn(ma)2, indicating that Zn(alx)2 possesses greater in vivo anti-diabetic activity than Zn(ma)2. In addition, Zn(alx)2 improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-Ay mice. On the basis of these observations, we conclude that the Zn(alx)2 complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.