Syntheses of Cu(II), Ni(II), and Zn(II) complexes with 2-acetylpyrazine N(4)-phenylthiosemicarbazone and evaluation of their antidiabetic effects

Abstract

The increasing number of patients with diabetes has recently become a serious problem following changes in diet and lifestyle. Various drugs are used to treat diabetes; however, there are serious concerns regarding their physical and mental side effects. Zinc, copper, and nickel are trace elements present in the body that are known to have insulin-like effects although nickel is not essential to mammals. Here, we focused on metal complexes with the 2-acetylpyrazine N(4)-phenylthiosemicarbazone (2-APTC) ligand, which has a six-coordinate octahedral structure with an S₂N₄-type coordination mode. For single oral administration experiments, [Zn(2-APTC)₂], zinc sulfate (10 mg Zn/kg) and [Cu(2-APTC)₂], and copper sulfate (3 mg Cu/kg) were orally administered to 5-week-old ddy mice fasted for 12 h. Moreover, of [Zn(2-APTC)₂] was administered daily to KK-A^y mice, a type 2 diabetes model. In a single oral administration experiment, [Zn(2-APTC)₂] showed a significant increase in plasma zinc concentration compared to zinc sulfate. Moreover, the 28-d administration of [Zn(2-APTC)₂] resulted in a significant decrease in the blood glucose level. This suggests that [Zn(2-APTC)₂] has a higher absorption of the complexes than [Cu(2-APTC)₂] after oral administration and is expected to have more antidiabetic activity. However, blood urea nitrogen, aspartate aminotransferase, and alanine transaminase levels increased, suggesting that [Zn(2-APTC)₂] administration affects liver and kidney functions. Moreover, hematoxylin and eosin staining showed that [Zn(2-APTC)₂] ameliorated fatty liver and exerted antidiabetic effects. Here, we report for the first time that a zinc complex with a six-coordinated octahedral structure, with 2-APTC as a ligand, exhibits antidiabetic effects.

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