YAHAGIHARA Naohisa Department of Materials Science, Teikyo University, 理工学部, 助教授 (40230271)
TSUKUBE Hiroshi Faculty of Science, Osaka City University, 理学部, 教授 (00144725)
SAKURAI Hiromu Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 薬学部, 教授 (30065916)
ADACHI Hidenari Sanyo Fine K. K., 研究開発部, 部長
|Budget Amount *help
¥12,400,000 (Direct Cost : ¥12,400,000)
Fiscal Year 1999 : ¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1998 : ¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1997 : ¥7,700,000 (Direct Cost : ¥7,700,000)
In this research, we synthesized oxovanadium (IV) (VO) complexes with several bis-amino acid derivatives of NィイD22ィエD2OィイD23ィエD2 donor sets, which were prepared by a convenient method developed by us, and evaluated firstly in vitro insulin-mimetic activities of the complexes using isolated rat adipocytes. This evaluation method, in which the inhibitory effects of the complexes on the release of free fatty acids from the adipocytes are examined, has been proposed to be useful to test and find insulin-mimetic compounds by Sakurai et al..
Among the complexes examined in in vitro, VO complex with N, N'-ethylenebis (glycine) (GeG) was found to have highest insulin-mimetic activities. On the other hand, VO complexes with pentadentate ligands (HeY, HeT and HeV) exhibited no activities. Furthermore, the complexes which contain D-amino acids were found to have higher insulin-mimetic activities than corresponding L-isomers. As a result of in vitro studies, we were successful in elucidating struct
ure-insulinomimetic activity relationships of VO complexes based on the absolute configuration, amino acid side chains, physicochemical properties of the complexes.
Secondly, we examined the serum glucose normalizing effects of VO (GeG) and VO (ィイD1mィエD1GeGィイD1mィエD1) (ィイD1mィエD1G=GィイD1mィエD1=N-methylglycine) that were the most and second most effective of the complexes evaluated in in vitro test. The high serum glucose levels in STZ-rats gradually dropped to the subnormal range (<200 mg/dl), after daily intraperitoneal injections of these complexes at the doses of 5 mg V/kg body weight, and the levels were maintained in several days even after ceasing administrations. BUN (blood urea nitrogen) levels in rats were not so high and body weights of rats did not decrease, suggesting the low toxicity of the complexes. However, the efficacies of these complexes against hyperglycemia of STZ-rat were, unfortunately, not better than that of VO-picolinato complex, which has been proposed to be one of the most hopeful agents of the world. Less