Evaluation of insulin-mimetic activities of vanadyl and zinc(II) complexes from the viewpoint of heterocyclic bidentate ligands.
Vanadyl sulfate (VOSO(4)) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO(4) 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 VOSO(4) 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 on 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 1-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 IC(50) 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.
Katoh
Akira
A
Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, 3-3-1 Kitamachi, Kichijoji, Musashino-shi, Tokyo, Japan. katoh@st.seikei.ac.jp
Matsumura
Yuriko
Y
Yoshikawa
Yutaka
Y
Yasui
Hiroyuki
H
Sakurai
Hiromu
H
D000818:Animals; D032701:Biomimetics; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D013329:Structure-Activity Relationship; D014639:Vanadium / Q000737:chemistry* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology
D006571:Heterocyclic Compounds; D007004:Hypoglycemic Agents; D007328:Insulin; D014639:Vanadium; D015032:Zinc