A [meso-tetrakis(4-sulfonatophenyl)porphyrinato]zinc(ii) complex as an oral therapeutic for the treatment of type 2 diabetic KKA(y) mice.
We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]zinc(II) ([Zn(tpps)]), and investigated its in vitro insulin-mimetic activity and in vivo hypoglycemic effect in type 2 diabetic KKA(y) mice. The results were compared with those of previously proposed insulin-mimetic zinc(II) complexes and zinc sulfate (ZnSO(4)). The in vitro insulin-mimetic activity of [Zn(tpps)] was considerably better than that of bis(allixinato)zinc(II) ([Zn(alx)(2)]), bis(maltolato)zinc(II) ([Zn(mal)(2)]), bis(2-aminomethylpyridinato)zinc(II) ([Zn(2-ampy)(2)](2+)), and ZnSO(4). In particular, the order of in vitro insulin-mimetic activity of the complexes was determined to be: [Zn(tpps)]>[Zn(alx)(2)]>[Zn(mal)(2)]>[Zn(2-ampy)](2+)>ZnSO(4). [Zn(tpps)] normalized the hyperglycemia of KKA(y) mice within 21 days when administered orally at doses of 10-20 mg (0.15-0.31 mmol) Zn per kg body mass for 28 days. In addition, metabolic syndromes such as insulin resistance, the degree of renal disturbance, and the degree of liver disturbance were significantly improved in [Zn(tpps)]-treated KKA(y) mice relative to those administered with saline and ZnSO(4). The improvement in diabetes was validated by the results of oral glucose-tolerance tests and the decrease in the HbA(1c) level observed. In contrast, ZnSO(4) and the ligand H(2)tpps did not lower the elevated blood glucose level under the same experimental conditions. Based on these observations, [Zn(tpps)] is proposed to be the first orally active zinc(II)-porphyrin complex for the efficacious treatment of not only type 2 diabetes but also metabolic syndromes in animals.
Saha
Tapan K
TK
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA. tksaha_ju@yahoo.com
Yoshikawa
Yutaka
Y
Sakurai
Hiromu
H
D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004333:Drug Administration Routes; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives; D008024:Ligands; D008665:Metalloporphyrins / Q000008:administration & dosage*; D051379:Mice; D011166:Porphyrins / Q000008:administration & dosage*; D013329:Structure-Activity Relationship; D013997:Time Factors; D015032:Zinc / Q000737:chemistry*; D019287:Zinc Sulfate / Q000737:chemistry
D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D008665:Metalloporphyrins; D011166:Porphyrins; C016136:tetraphenylporphine sulfonate; D019287:Zinc Sulfate; D015032:Zinc