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 (log P) 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- A(y) mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)(2) improved glucose tolerance in KK- A(y) 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- A(y) 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.
Adachi
Yusuke
Y
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, 607-8414 Kyoto, Japan.
Yoshida
Jiro
J
Kodera
Yukihiro
Y
Kato
Akira
A
Yoshikawa
Yutaka
Y
Kojima
Yoshitane
Y
Sakurai
Hiromu
H
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D004837:Epinephrine / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011753:Pyrones / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008024:Ligands; D009942:Organometallic Compounds; D011753:Pyrones; C499174:bis(allixinato)zinc; C008316:maltol; D005947:Glucose; D015032:Zinc; D004837:Epinephrine