Development of a novel antidiabetic zinc complex with an organoselenium ligand at the lowest dosage in KK-Ay mice

Diabetes mellitus (DM) is a considerably diagnosed metabolic disease and a serious problem worldwide. We prepared various zinc complexes and studied their potential for use as new antidiabetic agents. In this study, we synthesized a seleniferous zinc complex, di(2-selenopyridine-N-oxidato)zinc(II) ([ZPS]) that has a Zn(Se2O2) coordination mode. Analyses of structure-activity relationships between its insulin-like activity and the coordination mode of [ZPS]-related complexes showed that it had high insulin-like activity. Hypoglycemic effects of [ZPS] on type 2 diabetic KK-Ay mice were exerted at the lowest dose administered (1.25–2.5 mg Zn/kg body weight), unlike previously synthesized zinc complexes. Furthermore, [ZPS] afforded us a new advantage; we were able to investigate the tissue distribution of the ligand by measuring the amount of selenium in the organs of [ZPS]-treated mice. Gastrointestinal absorption and tissue penetration of zinc derived from [ZPS] in ddY mice, which was monitored using an isotope tracer technique, was significantly increased compared to that of ZnCl2. These results suggest that [ZPS] has superior antidiabetic effects compared to previously reported zinc complexes, and is thus a potential novel antidiabetic agent that facilitates the possibility of organoselenium ligands as new metal delivery systems for treating DM.

Graphical abstractA novel antidiabetic zinc complex ([ZPS]) was synthesized. The hypoglycemic effects of [ZPS] in type 2 diabetic KK-Ay mouse were exerted at the lowest doses than previously studied zinc complexes. The possibilities of [ZPS] and an organoselenium ligand as an antidiabetic agent and a metal delivery system, respectively, were reported.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A novel antidiabetic zinc complex with an organoselenium ligand was synthesized. ► [ZPS] exerted the higher hypoglycemic effects than previously studied zinc complexes. ► [ZPS] greatly enhanced the gastrointestinal absorption of zinc. ► We report the relations between dissociation and distribution of [ZPS]-derived zinc.