顺铂及三唑席夫碱铂配合物抑制PTPs活性的研究
发布时间：2019-02-19 17:06
【摘要】：恶性肿瘤严重威胁着人类生命健康,迄今为止其治疗方式还存在很多缺陷。抗肿瘤药物在肿瘤的临床治疗中发挥着重要作用,随着生命科学技术的不断深入,恶性肿瘤细胞内的信号转导、细胞周期调控等各种相互作用的基本过程正在被逐步阐明,新型分子靶向药物研究成为当前的热点。最近研究表明,蛋白酪氨酸磷酸酶(PTPs)的活性异常与恶性肿瘤的发生和发展有着密切的关系,已经成为抗肿瘤药物研究的一个新靶点,PTPs抑制剂研究也逐渐成为抗肿瘤药物发展的一个新方向。目前,关于PTPs金属配合物抑制剂的研究主要集中在钒、铜、锌等配合物上,然而针对靶向PTPs的铂配合物抗肿瘤药物研究在国内外还是空白。考虑到铂类化合物在恶性肿瘤的化学治疗中占据着重要地位,以及近期研究发现铂配合物也可能通过作用某些蛋白抑制肿瘤细胞的生长、繁殖现象。本论文以PTPs为靶点,设计、合成并表征了一系列新型多核铂类配合物,并且研究了该类配合物与顺铂等临床药物对PTPs活性的抑制作用及机理,主要研究内容和结果如下：1.研究了临床上公认的铂类药物(如顺铂、卡铂和奥沙利铂等)在体外对PTPs活性的抑制作用,结果表明,顺铂对PTPIB、TCPTP活性的抑制效果最好,而且其对PTPIB抑制的IC50值为TCPTP抑制的10倍,具有很好的选择性,同时细胞实验也表明,顺铂可以有效抑制肿瘤细胞内的PTPs活性。进一步的机理研究表明顺铂能够以非竞争模式抑制PTPIB,二者的键合比为1：1,该研究结果表明顺铂可能有一个新的抗肿瘤作用机理。2.合成表征了四个三唑席夫碱配体及其对应的双核铂配合物,成功获得到三个配合物晶体,研究了该类配合物对PTPs活性的抑制作用,结果表明配合物对PTPIB和TCPTP活性有一定的抑制作用,但其抑制能力弱于顺铂,荧光滴定实验显示其可能作用于PTP1B的活性位点。3.分析各个铂配合物结构与其活性之间的关系可以发现,与铂离子配位的离去基团的存在有利于提高铂配合物对PTPs活性的抑制能力,同时铂配合物的空间结构也会影响其抑制能力。这些结果为我们后续设计合成靶向PTPs抗肿瘤铂配合物提供了理论指导。
[Abstract]:Malignant tumor is a serious threat to human life and health, so far, there are still many defects in its treatment. Antitumor drugs play an important role in the clinical treatment of cancer. With the development of life science and technology, the basic processes of various interactions, such as signal transduction and cell cycle regulation in malignant tumor cells, are being elucidated step by step. The research of novel molecular targeted drugs has become a hot spot. Recent studies have shown that the abnormal activity of protein tyrosine phosphatase (PTPs) is closely related to the occurrence and development of malignant tumors, and has become a new target in the research of antitumor drugs. The study of PTPs inhibitors has gradually become a new direction in the development of anti-tumor drugs. At present, the studies on PTPs metal complex inhibitors are mainly focused on vanadium, copper, zinc and other complexes. However, the research on the antitumor drugs of platinum complexes targeting PTPs is still blank at home and abroad. Considering that platinum compounds play an important role in the chemotherapy of malignant tumors, it has been recently found that platinum complexes may inhibit the growth and reproduction of tumor cells by acting on some proteins. In this thesis, a series of novel polynuclear platinum complexes were designed, synthesized and characterized with PTPs as the target, and the inhibitory effect and mechanism of the complexes with cisplatin on PTPs activity were studied. The main contents and results are as follows: 1. The inhibitory effects of clinically recognized platinum drugs (such as cisplatin, carboplatin and oxaliplatin) on PTPs activity in vitro were studied. The results showed that cisplatin had the best inhibitory effect on PTPIB,TCPTP activity. The inhibition of IC50 on PTPIB was 10 times higher than that of TCPTP, and it had a good selectivity. The cell experiments also showed that cisplatin could effectively inhibit the PTPs activity in tumor cells. Further studies show that cisplatin can inhibit the binding ratio of PTPIB, to PTPIB, in a non-competitive mode with a ratio of 1: 1. The results indicate that cisplatin may have a new anti-tumor mechanism. 2. Four triazole Schiff base ligands and their corresponding binuclear platinum complexes were synthesized and characterized. Three complexes were successfully obtained. The inhibitory effects of these complexes on PTPs activity were studied. The results showed that the complexes had a certain inhibitory effect on the activities of PTPIB and TCPTP, but their inhibitory ability was weaker than that of cisplatin. Fluorescence titration showed that the complexes might act on the active sites of PTP1B. By analyzing the relationship between the structure and the activity of platinum complexes, it is found that the presence of leaving groups in coordination with platinum ions can improve the inhibition ability of platinum complexes on PTPs activity. At the same time, the space structure of platinum complex will also affect its inhibition ability. These results provide theoretical guidance for the subsequent design and synthesis of targeted PTPs antitumor platinum complexes.
【学位授予单位】：山西大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91;O641.4;R96
本文编号：2426690
[Abstract]:Malignant tumor is a serious threat to human life and health, so far, there are still many defects in its treatment. Antitumor drugs play an important role in the clinical treatment of cancer. With the development of life science and technology, the basic processes of various interactions, such as signal transduction and cell cycle regulation in malignant tumor cells, are being elucidated step by step. The research of novel molecular targeted drugs has become a hot spot. Recent studies have shown that the abnormal activity of protein tyrosine phosphatase (PTPs) is closely related to the occurrence and development of malignant tumors, and has become a new target in the research of antitumor drugs. The study of PTPs inhibitors has gradually become a new direction in the development of anti-tumor drugs. At present, the studies on PTPs metal complex inhibitors are mainly focused on vanadium, copper, zinc and other complexes. However, the research on the antitumor drugs of platinum complexes targeting PTPs is still blank at home and abroad. Considering that platinum compounds play an important role in the chemotherapy of malignant tumors, it has been recently found that platinum complexes may inhibit the growth and reproduction of tumor cells by acting on some proteins. In this thesis, a series of novel polynuclear platinum complexes were designed, synthesized and characterized with PTPs as the target, and the inhibitory effect and mechanism of the complexes with cisplatin on PTPs activity were studied. The main contents and results are as follows: 1. The inhibitory effects of clinically recognized platinum drugs (such as cisplatin, carboplatin and oxaliplatin) on PTPs activity in vitro were studied. The results showed that cisplatin had the best inhibitory effect on PTPIB,TCPTP activity. The inhibition of IC50 on PTPIB was 10 times higher than that of TCPTP, and it had a good selectivity. The cell experiments also showed that cisplatin could effectively inhibit the PTPs activity in tumor cells. Further studies show that cisplatin can inhibit the binding ratio of PTPIB, to PTPIB, in a non-competitive mode with a ratio of 1: 1. The results indicate that cisplatin may have a new anti-tumor mechanism. 2. Four triazole Schiff base ligands and their corresponding binuclear platinum complexes were synthesized and characterized. Three complexes were successfully obtained. The inhibitory effects of these complexes on PTPs activity were studied. The results showed that the complexes had a certain inhibitory effect on the activities of PTPIB and TCPTP, but their inhibitory ability was weaker than that of cisplatin. Fluorescence titration showed that the complexes might act on the active sites of PTP1B. By analyzing the relationship between the structure and the activity of platinum complexes, it is found that the presence of leaving groups in coordination with platinum ions can improve the inhibition ability of platinum complexes on PTPs activity. At the same time, the space structure of platinum complex will also affect its inhibition ability. These results provide theoretical guidance for the subsequent design and synthesis of targeted PTPs antitumor platinum complexes.
【学位授予单位】：山西大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91;O641.4;R96
【共引文献】
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1 李晨;代谢调控因子SIRT1基因多态性与2型糖尿病早期肾病的关联研究[D];青岛大学;2014年
2 黄立伟;化合物CXW增强细胞胰岛素反应性及其作用机制的实验研究[D];北京协和医学院;2014年
3 李宁;超声辅助提取青荚叶多酚工艺及抗氧化活性的研究[D];郑州大学;2014年
4 赵晓燕;老年痴呆病理与SUMO-1修饰的相关研究[D];复旦大学;2012年
5 徐斌强;肥胖患者精子蛋白酪氨酸磷酸酶1B异常高表达对精子顶体反应的影响[D];南京大学;2013年
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