生物小分子钒、铜、锌配合物抑制PTP1B的研究
发布时间：2019-06-30 22:10
【摘要】： 糖尿病及其并发症严重影响了人类的健康。随着科学技术的不断发展,人们对糖尿病的认识逐步加深。糖尿病主要分为Ⅰ型和Ⅱ型,其中Ⅱ型糖尿病约占90%,是一种常见的慢性疾病,是由于胰岛素分泌相对不足或胰岛素抵抗引起的。 近些年研究发现,蛋白酪氨酸磷酸酶1B(PTPlB)在胰岛素信号转导过程中起负调控作用,抑制PTP1B酶的活性可以有效地提高胰岛素的敏感性、增加血糖代谢,还可以抵抗由于食用高脂肪的食物引起的肥胖。因此,抑制PTP1B已经成为一种新型、有发展前景的治疗Ⅱ型糖尿病的方法之一 钒是人体必需的微量元素之一,具有类胰岛素性质,可以有效的降糖、降脂。然而无机钒酸盐不利于胃与肠的吸收而且在人体内会产生副作用,相比之下,有机钒配合物比无机钒配合物有更强的亲脂性,有利于提高钒的生物利用度,而且有些有机钒配合物的生物活性比无机钒离子强。 由于人体内存在大量氨基酸和其他有机小分子,进入人体的钒配合物可能与这些氨基酸或其他有机小分子发生配体交换,形成氨基酸或其他有机小分子钒配合物。对这些生物小分子钒配合物抑制PTP1B酶活性进行研究,有助于我们评估有机钒配合物在体内产生生物活性的效果。从这个目的出发,我们以一些氨基酸以及体内有机小分子为配体,模拟体内环境中这些生物小分子大大超过钒浓度的情况,与硫酸氧钒作用得到所需的配合物,’研究其对PTP1B的抑制作用。在此基础上进一步比较了相同配体的铜、锌配合物对PTP1B的活性抑制效果,主要工作如下： 1.合成了Na2[VO(Glu)2(CH3OH)].H2O配合物,运用元素分析、红外光谱、电喷雾质谱、电位滴定等方法对其固体结构和溶液组成进行了表征,实验结果表明,生理pH溶液中配合物组成的主要物种与固体粉末分析组成是一致的,并推测出配合物的可能结构。 2.研究了氧钒配合物对PTPlB酶活性抑制和选择性实验。结果表明,氨基酸-氧钒配合物的IC50值在0.13～1.05μM之间,具有高效的抑制作用,其抑制作用的大小主要受空间位阻和电子效应的影响；与HePTP、TCPTP、SHP-1的抑制作用相比,配合物对PTPlB有适当的选择性。虽然有机小分子-氧钒配合物的IC50值在0.29～21.49μM之间,与氨基酸-氧钒配合物抑制能力相比有所降低,但整体抑制效果还是比较强的。以Glu-VO(Ⅳ)为例进行抑制动力学,初步探索了Glu-VO(Ⅳ)与PTP1B酶的作用机理类型。结果表明,Glu-VO(Ⅳ)对PTP1B酶表现为竞争型抑制。另外,荧光实验揭示出,结合常数随着温度的升高而降低,证明形成非荧光复合物引起静态猝灭,在此基础上,根据van't Hoff方程计算得到热力学参数表明,Glu-VO(Ⅳ)与PTP1B酶形成的复合物是疏水力和静电引力共同作用的结果。 3.选取相同配体与锌、铜分别形成配合物,研究其对PTP1B的抑制作用,并与钒配合物的抑制作用作比较,实验结果表明amino acids-Cu(Ⅱ)配合物的抑制能力略低于钒配合物但明显强于锌配合物。进一步的作用机理实验结果表明,虽然Glu-Zn(Ⅱ)与PTP1B酶之间的猝灭属于静态猝灭作用,但是结合位点数是1,结合常数的数量级是106,这说明Glu-Zn(Ⅱ)和Glu-VO(Ⅳ)与PTP1B酶的结合模式可能是不同的。
[Abstract]:Diabetes and its complications seriously affect human health. With the development of science and technology, people's understanding of diabetes is gradually deepened. Diabetes is mainly divided into type I and type II, of which type II diabetes is about 90%, is a common chronic disease, which is caused by relative deficiency of insulin or insulin resistance. In recent years, it has been found that protein tyrosine phosphatase 1B (PTPlB) plays a negative regulatory role in the process of insulin signal transduction, inhibiting the activity of PTP1B enzyme can effectively improve the sensitivity of insulin, increase blood glucose metabolism, and resist the food caused by eating high fat Therefore, the inhibition of PTP1B has become a new and promising treatment for type II diabetes. one of the essential trace elements of the human body, but the inorganic salt is not beneficial to the absorption of the stomach and the intestine, and the side effect can be generated in the human body, in contrast, the organic selenium complex has stronger lipophilicity than the inorganic salt complex, and is beneficial to the improvement the bioavailability of the enzyme, and the biological activity of some of the organic sulfur complexes Due to the presence of a large amount of amino acids and other organic small molecules in the human body, the complex complex entering the human body may be subjected to ligand exchange with these amino acids or other organic small molecules to form an amino acid or Other organic small molecular weight complexes. The inhibition of PTP1B enzyme activity by these small molecular weight complexes helps us to assess the presence of the organometallic complex in The effect of biological activity in the body is obtained. From this point of view, we use some amino acids as well as the organic small molecules in the body as the ligand to simulate the conditions in the in-vivo environment that the small molecules in the in-vivo environment greatly exceed the oxygen concentration, and react with the sulfuric acid The inhibitory effect of copper and zinc complexes of the same ligand on PTP1B was further compared. The main work is as follows:1. Synthesis of Na2[VO (Glu)2 (CH3OH)]. H2O complex, application The solid structure and the solution composition were characterized by elemental analysis, infrared spectroscopy, electrospray mass spectrometry, potentiometric titration and the like. The experimental results showed that the composition of the complex in the physiological pH solution The composition of the analysis of the species and the solid powder is one The results showed that the IC50 value of the amino acid-oxygen complex complex was 0.13. The inhibitory effect is mainly influenced by steric hindrance and electron effect, and the complex is suitable for PTPlB as compared with the inhibition of HPTP, TCPTP and SHP-1. The value of C50 is between 0.29 and 21.49. m, which is lower than that of the amino acid-oxygen-containing complex, but the overall inhibitory effect is still relatively strong. The inhibition of Glu-VO (IV) is taken as an example, and the Glu-VO (IV) is preliminarily explored. The results show that Glu-VO (鈪，
本文编号：2508296
[Abstract]:Diabetes and its complications seriously affect human health. With the development of science and technology, people's understanding of diabetes is gradually deepened. Diabetes is mainly divided into type I and type II, of which type II diabetes is about 90%, is a common chronic disease, which is caused by relative deficiency of insulin or insulin resistance. In recent years, it has been found that protein tyrosine phosphatase 1B (PTPlB) plays a negative regulatory role in the process of insulin signal transduction, inhibiting the activity of PTP1B enzyme can effectively improve the sensitivity of insulin, increase blood glucose metabolism, and resist the food caused by eating high fat Therefore, the inhibition of PTP1B has become a new and promising treatment for type II diabetes. one of the essential trace elements of the human body, but the inorganic salt is not beneficial to the absorption of the stomach and the intestine, and the side effect can be generated in the human body, in contrast, the organic selenium complex has stronger lipophilicity than the inorganic salt complex, and is beneficial to the improvement the bioavailability of the enzyme, and the biological activity of some of the organic sulfur complexes Due to the presence of a large amount of amino acids and other organic small molecules in the human body, the complex complex entering the human body may be subjected to ligand exchange with these amino acids or other organic small molecules to form an amino acid or Other organic small molecular weight complexes. The inhibition of PTP1B enzyme activity by these small molecular weight complexes helps us to assess the presence of the organometallic complex in The effect of biological activity in the body is obtained. From this point of view, we use some amino acids as well as the organic small molecules in the body as the ligand to simulate the conditions in the in-vivo environment that the small molecules in the in-vivo environment greatly exceed the oxygen concentration, and react with the sulfuric acid The inhibitory effect of copper and zinc complexes of the same ligand on PTP1B was further compared. The main work is as follows:1. Synthesis of Na2[VO (Glu)2 (CH3OH)]. H2O complex, application The solid structure and the solution composition were characterized by elemental analysis, infrared spectroscopy, electrospray mass spectrometry, potentiometric titration and the like. The experimental results showed that the composition of the complex in the physiological pH solution The composition of the analysis of the species and the solid powder is one The results showed that the IC50 value of the amino acid-oxygen complex complex was 0.13. The inhibitory effect is mainly influenced by steric hindrance and electron effect, and the complex is suitable for PTPlB as compared with the inhibition of HPTP, TCPTP and SHP-1. The value of C50 is between 0.29 and 21.49. m, which is lower than that of the amino acid-oxygen-containing complex, but the overall inhibitory effect is still relatively strong. The inhibition of Glu-VO (IV) is taken as an example, and the Glu-VO (IV) is preliminarily explored. The results show that Glu-VO (鈪，
本文编号：2508296
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