Evaluation of insulin-mimetic activities of vanadyl and zinc(II) complexes from the viewpoint of heterocyclic bidentate ligands

Vanadyl sulfate (VOSO4) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO4 improved the type 2 diabetic state with respect to plasma glucose, HbA(1c), and fructosamine levels. The development of toxicity by increasing the administration Of VOSO4 should be avoided. One method was the utilization of vanadyl complexes with coordination compounds that are low-toxic and low-molecular-weight ligands to enhance the permeation of the metal ion to lipid bilayer membrane. Over a decade we have focused oil a variety of heterocyclic compounds as bidentate ligands for metal ions. Vanadyl and zinc(II) complexes of 1-substituted 3-hydroxy-2-methyl-4(1H)-pyridinethiones, 4,5,6-substituted 1-hydroxy-2(1H)-pyrimidinones, 4-(p-substituted)phenyl-3-hydroxythiazole-2(3H)-thiones. 3-hydroxypyrone, 1-alkyl- or 1-phenylalkyl-3-hydroxy-2(1H)-pyridinethiones, optically active I-substituted 3-hydroxy-4(1H)-pyridinethiones, and 5-dialkylsulfonamido- or 5,7-bis(dialkylsulfonamido)-8-hydroxyquinolines were prepared, and their insulin-mimetic activities were evaluated in terms of IC50 values which stand for a 50% inhibitory concentration of the free fatty acid release from isolated rat adipocytes. In this article, the relationship between the insulin-mimetic activity and the partition coefficient, the chirality, the substituent effect, molecular weight, the pK(a), value, and the coordination mode was discussed. In vivo blood glucose-lowering effects of the vanadyl complex with 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone in streptozotocin (STZ)-induced diabetic rats and the zinc(II) complexes with 4-(p-chlorophenyl)thiazole- and 4-methylthiazole-2(3H)-thione in KK-A(y) mice were also discussed. (C) 2008 Elsevier Inc. All rights reserved.