生物小分子釩、銅、鋅配合物抑制PTP1B的研究
發(fā)布時間：2019-06-30 22:10
【摘要】： 糖尿病及其并發(fā)癥嚴重影響了人類的健康。隨著科學技術的不斷發(fā)展,人們對糖尿病的認識逐步加深。糖尿病主要分為Ⅰ型和Ⅱ型,其中Ⅱ型糖尿病約占90%,是一種常見的慢性疾病,是由于胰島素分泌相對不足或胰島素抵抗引起的。 近些年研究發(fā)現(xiàn),蛋白酪氨酸磷酸酶1B(PTPlB)在胰島素信號轉(zhuǎn)導過程中起負調(diào)控作用,抑制PTP1B酶的活性可以有效地提高胰島素的敏感性、增加血糖代謝,還可以抵抗由于食用高脂肪的食物引起的肥胖。因此,抑制PTP1B已經(jīng)成為一種新型、有發(fā)展前景的治療Ⅱ型糖尿病的方法之一 釩是人體必需的微量元素之一,具有類胰島素性質(zhì),可以有效的降糖、降脂。然而無機釩酸鹽不利于胃與腸的吸收而且在人體內(nèi)會產(chǎn)生副作用,相比之下,有機釩配合物比無機釩配合物有更強的親脂性,有利于提高釩的生物利用度,而且有些有機釩配合物的生物活性比無機釩離子強。 由于人體內(nèi)存在大量氨基酸和其他有機小分子,進入人體的釩配合物可能與這些氨基酸或其他有機小分子發(fā)生配體交換,形成氨基酸或其他有機小分子釩配合物。對這些生物小分子釩配合物抑制PTP1B酶活性進行研究,有助于我們評估有機釩配合物在體內(nèi)產(chǎn)生生物活性的效果。從這個目的出發(fā),我們以一些氨基酸以及體內(nèi)有機小分子為配體,模擬體內(nèi)環(huán)境中這些生物小分子大大超過釩濃度的情況,與硫酸氧釩作用得到所需的配合物,’研究其對PTP1B的抑制作用。在此基礎上進一步比較了相同配體的銅、鋅配合物對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,運用元素分析、紅外光譜、電噴霧質(zhì)譜、電位滴定等方法對其固體結(jié)構和溶液組成進行了表征,實驗結(jié)果表明,生理pH溶液中配合物組成的主要物種與固體粉末分析組成是一致的,并推測出配合物的可能結(jié)構。 2.研究了氧釩配合物對PTPlB酶活性抑制和選擇性實驗。結(jié)果表明,氨基酸-氧釩配合物的IC50值在0.13～1.05μM之間,具有高效的抑制作用,其抑制作用的大小主要受空間位阻和電子效應的影響；與HePTP、TCPTP、SHP-1的抑制作用相比,配合物對PTPlB有適當?shù)倪x擇性。雖然有機小分子-氧釩配合物的IC50值在0.29～21.49μM之間,與氨基酸-氧釩配合物抑制能力相比有所降低,但整體抑制效果還是比較強的。以Glu-VO(Ⅳ)為例進行抑制動力學,初步探索了Glu-VO(Ⅳ)與PTP1B酶的作用機理類型。結(jié)果表明,Glu-VO(Ⅳ)對PTP1B酶表現(xiàn)為競爭型抑制。另外,熒光實驗揭示出,結(jié)合常數(shù)隨著溫度的升高而降低,證明形成非熒光復合物引起靜態(tài)猝滅,在此基礎上,根據(jù)van't Hoff方程計算得到熱力學參數(shù)表明,Glu-VO(Ⅳ)與PTP1B酶形成的復合物是疏水力和靜電引力共同作用的結(jié)果。 3.選取相同配體與鋅、銅分別形成配合物,研究其對PTP1B的抑制作用,并與釩配合物的抑制作用作比較,實驗結(jié)果表明amino acids-Cu(Ⅱ)配合物的抑制能力略低于釩配合物但明顯強于鋅配合物。進一步的作用機理實驗結(jié)果表明,雖然Glu-Zn(Ⅱ)與PTP1B酶之間的猝滅屬于靜態(tài)猝滅作用,但是結(jié)合位點數(shù)是1,結(jié)合常數(shù)的數(shù)量級是106,這說明Glu-Zn(Ⅱ)和Glu-VO(Ⅳ)與PTP1B酶的結(jié)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，
本文編號：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，
本文編號：2508296
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