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研究论文

新型抗糖尿病铬(III)配合物的合成和生物活性及机理探究

董金龙a,b, 沈腊珍a, 文斌a, 宋珍a, 冯俊杰a, 梁钢c, 刘斌b, 杨斌盛b   

  1. a 太原师范学院化学系 晋中 030619;
    b 山西大学分子科学研究所 化学生物学与分子工程教育部重点实验室 太原 03006;
    c 山西医科大学第一医院病理科 太原 030001
  • 发布日期:2020-09-04
  • 通讯作者: 董金龙, 杨斌盛 E-mail:dongjinlong20123@163.com;yangbs@sxu.edu.cn
  • 基金资助:
    国家自然基金(No.21571117,21701121),山西省自然基金(No.201801D121064),山西高校科技项目(No.2019L0818)和太原师范学院大学生创新创业项目(No.CXCY1905).

Synthesis of A Novel Anti-diabetes Chromium(III) Complex and Investigation of Its Biological Activity and Mechanism

Dong Jinlonga,b, Shen Lazhena, Wen Bina, Song Zhena, Feng Junjiea, Liang Gangc, Liu Binb, Yang Binshengb   

  1. a Department of Chemistry, Taiyuan Normal University, Jinzhong 030619;
    b Institute of Molecular Science, Key Laboratory of Chemical Biology of Molecular Engineering of Education Ministry, Shanxi University, Taiyuan 030006;
    c Department of Pathology, First Hospital of Shanxi Medical University, Taiyuan 030001
  • Published:2020-09-04

为了寻找新型的抗糖尿病分子,以苯乙双胍为前体,制备了苯乙双胍铬(III)配合物通过元素分析、摩尔电导率、电喷雾质谱、红外光谱、紫外可见光谱和核磁共振波谱对配合物的结构进行了表征,并研究了配合物在不同温度、不同pH值下溶液的稳定性、与H2O2的反应性和形貌。同时,构建了糖尿病C57小鼠模型,研究了其生物活性和毒性。结果证明,配合物对其活性指标均有好的抑制作用,保留了苯乙双胍的降糖性质,对机体是无毒的,并且通过MTT实验说明配合物的生物相容性较好,实现了金属配合物降糖与控脂的多功能化应用。在此基础上,通过光谱法研究了配合物与胰高血糖素的相互作用,表明配合物对胰高血糖素是静态猝灭以较强的作用力结合,条件结合常数为1.29×105 L/mol,结合位点数约为1,初步提出了配合物的新的降糖机制。

关键词: 苯乙双胍铬, 糖尿病, 生物活性, 胰高血糖素, 毒性

In order to search for novel anti-diabetes molecules, phenformin (Phf) was used as precursors to prepare chromium(III) complex at room temperature, [Cr(Phf)3]Cl3, which was characterized by elemental analysis (EA), molar conductivity (MC), electrospray ionization mass spectrometry (ESI-MS), infrared (IR), UV-vis and NMR spectroscopy. In this work, the stability of solutions at different temperatures and pH values, reactivity with H2O2, scanning electron microscopy (SEM) and thermal analyses (TG/DTG) of complex were yet discussed. Meanwhile, C57 diabetic mouse model induced by diet combined with streptozocin (STZ) was established to explore in detail its biological activity from the aspects of fasting blood glucose (FBG), fasting serum insulin (FINS), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL–c), low density lipoprotein cholesterol (LDL–c) levels, and oral toxicity. Then, to explore the biological hypoglycemic mechanism of the complex, the interaction between the complex and glucagon was studied at 37 ±0.5 ℃ in Phosphate Buffer Saline (PBS) buffer at pH 7.4 by fluorescence spectra, the conditional binding constant K 1.29×105 L/mol, the number of binding sites n 1, and it was the static quenching. As a result, the complex exhibited good physical and chemical properties, beneficial function on blood glucose and lipid metabolism for Type II Diabetes mellitus (T2DM), retained the glucose-lowering properties of Phf, proposed the glucose-lowering mechanism of the complex, and achieved the multi-functional application of metal complex in glucose-lowering and lipid-controlling. Furthermore, oral toxicity results showed that the complex had no toxicity on all organs of mice. Methyl Thiazolyl Tetrazolium (MTT) assays also showed the complex exhibited lower cytotoxicity than the positive control CrCl3 and Phf. Taken together, these results demonstrated that complex might be a potential candidate for novel anti–diabetic drug development, and non–toxic. It may also provide a new idea for the prevention and treatment of type 2 diabetes.

Key words: chromium(III) phenformin, diabetes, biology activity, glucagon, toxicity