关白附中基质金属蛋白酶抑制剂及金属离子对基质金属蛋白酶抑制作用的研究
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摘要
基质金属蛋白酶(MMPs)是一类依赖于Zn~(2+)、有降解细胞外基质(ECM)能力的内肽酶家族。MMPs参与了细胞凋亡、形态发生、增殖和发育等一系列病理和生理过程，其抑制剂对于包括癌症、心血管疾病、关节炎、眼病、免疫系统疾病、妇科疾病、皮肤病等许多重要疾病的药物治疗具有广阔的前景。从天然植物提取物中筛选MMPs抑制剂，并开发新药已成为该领域的研究热点。本研究以MMPs为分子靶点，通过水提醇沉、大孔树脂分离等手段，应用酶学方法，追踪分离关白附中抑制MMP-16活性的有效成分，对分出的单体进行结构表征、细胞实验、抑菌活性等研究，并对部分一价、二价、三价及稀土金属离子对MMPs的抑制作用、抑菌活性等进行了研究。
论文主要包括以下几部分：
对关白附、基质金属蛋白酶、基质金属蛋白酶抑制剂及金属离子的生物活性等四方面的国内外研究现状进行概述。
首次分离得到关白附中MMP-16的抑制单体，IC_(50)为3．4μmol／L，实验表明该单体是关白附中MMP-16的主要抑制剂。红外表征、元素分析、原子发射、性质实验、单晶衍射等鉴定结果表明该单体为十二水合硫酸铝铵(NH_4Al(SO_4)_2·12H_2O)。选择含有NH_4~+、Al~(3+)、SO_4~(2-)的化合物(或复盐)，考察它们对MMP-16的抑制活性，结果表明NH_4Al(SO_4)_2·12H_2O中抑制MMPs的活性离子为Al~(3+)。进一步的研究表明该单体对多种类型的MMPs(如MMP-2、MMP-9、MMP-13、MMP-3)均有良好的抑制作用(IC_(50)均小于10μmol／L)，并且细胞实验的结果表明该单体对癌症的浸润也具有抑制作用，说明该单体具有开发为抗癌药物的可能性。实验还考察了关白附提取物及活性单体对几种细菌的抑制作用，结果发现关白附中主要抑菌活性单体也为NH_4Al(SO_4)_2·12H_2O，并推测其活性基团为Al~(3+)。
考察了部分金属离子对MMP-16的抑制活性，发现所考察的一价、二价金属离子对MMP-16基本无活性，三价金属离子及稀土金属离子对MMP-16均有良好的抑制活性，且稀土金属离子对MMP-16的抑制作用呈现出一定的规律性，即分别在轻、中、重稀土金属组中，对MMP-16的抑制活性随着原子序数的增加而减小。同时考察了金属离子对细菌的抑制作用，结果发现除三价金属离子盐(包括所考察的稀土金属离子)对各种细菌都有良好的抑制活性外，某些一价、二价金属盐对细菌也有一定的抑制作用。
Matrix metalloproteinases (MMPs) are Zn~(2+)-dependent endopeptidases family, which are capable of collectively degrading all kinds of extracellular matrix proteins. MMPs involved in a series of pathological and physiological processes including apoptosis, morphogenesis, proliferation and upgrowth. It seems that matrix metalloroteinase inhibitors have broad potentials in curing many important diseases including cancer, cardiovascular disease, arthritis, eye disease, immune system diseases, gynecological diseases and skin diseases. It is attractive that screening of compounds against MMPs from the natural plant extracts and developing them to some new drugs. In this dissertation, with MMPs as the target, by using the polygona-polysaccharosel, macroporous resin separation and enzymologic techniques, the active ingredients of Aconitum coreanum to MMP-16 were tracked and separated. The structure of active compound was identified, and its antibacterial activity were also explored. The inhibitory activity of trivalent, divalent and one valence metal ions and and rare earth metal ions to MMPs and bacteria was also studied.
The main contents of this study include:
In this dissertation, the research work in domestic and international studies on Aconitum coreanum, matrix metalloproteinase, matrix metalloproteinase inhibitors and metal ions wasreviewed.
The monomer which can inhibit MMP-16 was isolated from Aconitum coreanum firstly,the experiment results show that the monomer was the main MMP-16 inhibitor in the Aconitum coreanum. The monomer was identified by IR, elemental analysis and atomic emission, the results suggested that it was dodecahydrate ammonium aluminum sulfate (NH_4Al(SO_4)_2·12H_2O). The compounds (or complex salt) containing NH_4~+, Al~(3+), SO_4~(2-) were selected to study their inhibitory activity to MMP-16, the result suggested that the active group of NH_4Al(SO_4)_2·12H_2O to MMP-16 was Al~(3+). Further studies have shown that the monomer also had strong inhibitory activity(IC_(50) less than 10μmol/L) to other MMPs (such as MMP-2、MMP-9、MMP-13、MMP-3) and its effect to cell morphology showed that it had inhibitory activity to the invasion of cancer. Therefore the monomer has the possibility to be anti-cancer drugs. The inhibitory activity of Aconitum coreanum extract and active monomer to several bacteria were also studied. The result showed that the main active monomer of Aconitum coreanum was NH_4Al(SO_4)_2·12H_2O also, and its active group was Al~(3+).
The inhibitory activity of some metal ions to MMP-16 was studied. The result showed that trivalent metal ions and rare earth metal ions had inhibitory activity to MMP-16 and divalent, one valence metal ions had no activity. The inhibitory activity of the rare earth metal ions to MMP-16 showed a certain degree of regularity, that was, in the group of LREEs, MREEs and HREEs, their inhibitory activity to MMP-16 decreased with the increase in the atomic number increaseing. At the same time, the inhibitory activity of some metal ions to bacteria was studied and the result showed that not only trivalent metal ion (including rare earth metal ions) had inhibitory activity to bacteria but also divalent and a divalent metal ions had a certain extent inhibitory activity to bacteria.
论文主要包括以下几部分：
对关白附、基质金属蛋白酶、基质金属蛋白酶抑制剂及金属离子的生物活性等四方面的国内外研究现状进行概述。
首次分离得到关白附中MMP-16的抑制单体，IC_(50)为3．4μmol／L，实验表明该单体是关白附中MMP-16的主要抑制剂。红外表征、元素分析、原子发射、性质实验、单晶衍射等鉴定结果表明该单体为十二水合硫酸铝铵(NH_4Al(SO_4)_2·12H_2O)。选择含有NH_4~+、Al~(3+)、SO_4~(2-)的化合物(或复盐)，考察它们对MMP-16的抑制活性，结果表明NH_4Al(SO_4)_2·12H_2O中抑制MMPs的活性离子为Al~(3+)。进一步的研究表明该单体对多种类型的MMPs(如MMP-2、MMP-9、MMP-13、MMP-3)均有良好的抑制作用(IC_(50)均小于10μmol／L)，并且细胞实验的结果表明该单体对癌症的浸润也具有抑制作用，说明该单体具有开发为抗癌药物的可能性。实验还考察了关白附提取物及活性单体对几种细菌的抑制作用，结果发现关白附中主要抑菌活性单体也为NH_4Al(SO_4)_2·12H_2O，并推测其活性基团为Al~(3+)。
考察了部分金属离子对MMP-16的抑制活性，发现所考察的一价、二价金属离子对MMP-16基本无活性，三价金属离子及稀土金属离子对MMP-16均有良好的抑制活性，且稀土金属离子对MMP-16的抑制作用呈现出一定的规律性，即分别在轻、中、重稀土金属组中，对MMP-16的抑制活性随着原子序数的增加而减小。同时考察了金属离子对细菌的抑制作用，结果发现除三价金属离子盐(包括所考察的稀土金属离子)对各种细菌都有良好的抑制活性外，某些一价、二价金属盐对细菌也有一定的抑制作用。
Matrix metalloproteinases (MMPs) are Zn~(2+)-dependent endopeptidases family, which are capable of collectively degrading all kinds of extracellular matrix proteins. MMPs involved in a series of pathological and physiological processes including apoptosis, morphogenesis, proliferation and upgrowth. It seems that matrix metalloroteinase inhibitors have broad potentials in curing many important diseases including cancer, cardiovascular disease, arthritis, eye disease, immune system diseases, gynecological diseases and skin diseases. It is attractive that screening of compounds against MMPs from the natural plant extracts and developing them to some new drugs. In this dissertation, with MMPs as the target, by using the polygona-polysaccharosel, macroporous resin separation and enzymologic techniques, the active ingredients of Aconitum coreanum to MMP-16 were tracked and separated. The structure of active compound was identified, and its antibacterial activity were also explored. The inhibitory activity of trivalent, divalent and one valence metal ions and and rare earth metal ions to MMPs and bacteria was also studied.
The main contents of this study include:
In this dissertation, the research work in domestic and international studies on Aconitum coreanum, matrix metalloproteinase, matrix metalloproteinase inhibitors and metal ions wasreviewed.
The monomer which can inhibit MMP-16 was isolated from Aconitum coreanum firstly,the experiment results show that the monomer was the main MMP-16 inhibitor in the Aconitum coreanum. The monomer was identified by IR, elemental analysis and atomic emission, the results suggested that it was dodecahydrate ammonium aluminum sulfate (NH_4Al(SO_4)_2·12H_2O). The compounds (or complex salt) containing NH_4~+, Al~(3+), SO_4~(2-) were selected to study their inhibitory activity to MMP-16, the result suggested that the active group of NH_4Al(SO_4)_2·12H_2O to MMP-16 was Al~(3+). Further studies have shown that the monomer also had strong inhibitory activity(IC_(50) less than 10μmol/L) to other MMPs (such as MMP-2、MMP-9、MMP-13、MMP-3) and its effect to cell morphology showed that it had inhibitory activity to the invasion of cancer. Therefore the monomer has the possibility to be anti-cancer drugs. The inhibitory activity of Aconitum coreanum extract and active monomer to several bacteria were also studied. The result showed that the main active monomer of Aconitum coreanum was NH_4Al(SO_4)_2·12H_2O also, and its active group was Al~(3+).
The inhibitory activity of some metal ions to MMP-16 was studied. The result showed that trivalent metal ions and rare earth metal ions had inhibitory activity to MMP-16 and divalent, one valence metal ions had no activity. The inhibitory activity of the rare earth metal ions to MMP-16 showed a certain degree of regularity, that was, in the group of LREEs, MREEs and HREEs, their inhibitory activity to MMP-16 decreased with the increase in the atomic number increaseing. At the same time, the inhibitory activity of some metal ions to bacteria was studied and the result showed that not only trivalent metal ion (including rare earth metal ions) had inhibitory activity to bacteria but also divalent and a divalent metal ions had a certain extent inhibitory activity to bacteria.
引文
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