Development of new insulinomimetic zinc(II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies
Development of new insulinomimetic zinc(II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies
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DOI：
10.1007/s007750100266
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发表时间：
2002-02
期刊：
影响因子：
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通讯作者：
Y. Yoshikawa;Eriko Ueda;K. Kawabe;H. Miyake;Toshikazu Takino;H. Sakurai;Y. Kojima
中科院分区：
文献类型：
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作者：
Y. Yoshikawa;Eriko Ueda;K. Kawabe;H. Miyake;Toshikazu Takino;H. Sakurai;Y. Kojima
合成了三种锌(N2O)配位模式的吡啶甲酸及其衍生物的锌(II)配合物，并通过体内外研究评价了它们的胰岛素仿生活性。通过在吡啶甲酸酯配体(PIC)中引入给电子基，制备了双(6-或3-甲基吡啶甲酸)锌(II)配合物[分别为锌(6-Mpa)2或锌(3-Mpa)2]。锌(6-Mpa)_2络合物以水加成物[Zn(6-Mpa)_2(H_2O)]·H_2O的形式结晶，其中两个6-Mpa的羧酸根和两个吡啶氮与水中的氧配位形成具有三方双锥构型的锌(II)。通过体外评价肾上腺素对大鼠脂肪细胞释放游离脂肪酸(FFA)的抑制作用，发现锌(PIC)2、锌(6-Mpa)2和锌(3-Mpa)2的胰岛素样活性(IC50分别为0.64±0.13、0.31±0.05和0.40±0.07 mM)高于VOSO4(IC50=1.00 mM)和ZnSO4(IC50=1.58±0.05 mM)。然后，对KK-Aymice合并2型糖尿病的KK-Aymice患者，以3.0 mg(45.9 mg/kg体重)的锌(45.9 mg/kg体重)，连续14天给药，发现在给药过程中，遗传性高血糖水平降低。口服糖耐量试验证实糖尿病改善。
Three zinc(II) complexes of picolinic acid and its derivatives with a Zn(N2O2) coordination mode were prepared and evaluated for their insulinomimetic activities by in vitro and in vivo studies. By introducing an electron-donating methyl group into the picolinate ligand (pic), bis(6- or 3-methylpicolinato)zinc(II) complexes [Zn(6-mpa)2or Zn(3-mpa)2, respectively] were prepared. The Zn(6-mpa)2complex was crystallized as a water adduct [Zn(6-mpa)2(H2O)]·H2O, in which two carboxylate oxygens and two pyridine nitrogens of 6-mpa and a water oxygen coordinate to a zinc(II) with a trigonal bipyramidal geometry. By in vitro evaluation of the inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, the insulinomimetic activities of Zn(pic)2, Zn(6-mpa)2, and Zn(3-mpa)2(IC50=0.64±0.13, 0.31±0.05, and 0.40±0.07 mM, respectively) were found to be higher than those of VOSO4(IC50=1.00 mM) and ZnSO4(IC50=1.58±0.05 mM) in terms of IC50value, the 50% inhibition concentrations for the FFA release from the adipocytes. Then, Zn(6-mpa)2, which exhibited the highest in vitro insulinomimetic activity among three complexes examined, was given at a dose of 3.0 mg (45.9 µmol) Zn/kg body weight to KK-Aymice with type 2 diabetes mellitus by daily intraperitoneal injections for 14 days and it was found that the hereditary high blood glucose levels were lowered during the administration of the complex. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.