Yoshikawa Yutaka, Adachi Yusuke, Yasui Hiroyuki, Hattori Masakazu, Sakurai Hiromu
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Japan.
Chem Pharm Bull (Tokyo). 2011;59(8):972-7. doi: 10.1248/cpb.59.972.
In recent years, the number of patients suffering from diseases, such as cancer, apoplexy, osteoporosis, hypertension, and type 2 diabetes mellitus is increasing worldwide. Type 2 diabetes, a lifestyle-related disease, is recognized as a serious disease. Various types of pharmaceutics for diabetes have been used. Since the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized for many years, we have been developing the anti-diabetic metal complexes as new candidates. We found that several zinc(II) (Zn) complexes exhibit glucose-lowering activity for treating type 2 diabetes. High doses of salicylates have been known to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients. These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating type 2 diabetes. Because aspirin, acetyl salicylic acid, has a chelating ability, we used it as a ligand to Zn. Several Zn-salicylate complexes were prepared and their biological activities were examined in this study. The complexes with an electron-withdrawing group in the ligand exhibited higher in vitro insulinomimetic activity than those of Zn complexes with an electron-donating group in the ligand. When bis(aspirinato)Zn (Zn(asp)₂) complex was orally administered on KK-A(y) mice with hereditary type 2 diabetes, the diabetic state was improved. In addition, this complex exhibited normalizing effects on serum adiponectin level and high blood pressure in metabolic syndrome. In conclusion, Zn(asp)₂ complex is newly proposed as a potent anti-diabetic and anti-metabolic syndrome agent.
近年来，在全球范围内，患有癌症、中风、骨质疏松症、高血压和2型糖尿病等疾病的患者数量正在增加。2型糖尿病是一种与生活方式相关的疾病，被认为是一种严重疾病。已经使用了各种类型的糖尿病药物。由于糖尿病与钒、铜和锌离子等生物金属之间的关系多年来已被人们所认识，我们一直在开发抗糖尿病金属配合物作为新的候选药物。我们发现几种锌（II）（Zn）配合物对治疗2型糖尿病具有降血糖活性。已知高剂量的水杨酸盐可逆转2型糖尿病患者的高血糖和高胰岛素血症。这些发现强烈表明，锌和水杨酸盐联合使用在治疗2型糖尿病方面具有协同作用。由于阿司匹林，即乙酰水杨酸，具有螯合能力，我们将其用作锌的配体。本研究制备了几种锌 - 水杨酸盐配合物并检测了它们的生物活性。配体中带有吸电子基团的配合物在体外比配体中带有供电子基团的锌配合物表现出更高的胰岛素模拟活性。当将双（阿司匹林根）锌（Zn（asp）₂）配合物口服给予遗传性2型糖尿病的KK - A（y）小鼠时，糖尿病状态得到改善。此外，该配合物对代谢综合征中的血清脂联素水平和高血压具有正常化作用。总之，Zn（asp）₂配合物被新提议作为一种有效的抗糖尿病和抗代谢综合征药物。
