順鉑及三唑席夫堿鉑配合物抑制PTPs活性的研究
發(fā)布時間：2019-02-19 17:06
【摘要】：惡性腫瘤嚴(yán)重威脅著人類生命健康,迄今為止其治療方式還存在很多缺陷�？鼓[瘤藥物在腫瘤的臨床治療中發(fā)揮著重要作用,隨著生命科學(xué)技術(shù)的不斷深入,惡性腫瘤細(xì)胞內(nèi)的信號轉(zhuǎn)導(dǎo)、細(xì)胞周期調(diào)控等各種相互作用的基本過程正在被逐步闡明,新型分子靶向藥物研究成為當(dāng)前的熱點。最近研究表明,蛋白酪氨酸磷酸酶(PTPs)的活性異常與惡性腫瘤的發(fā)生和發(fā)展有著密切的關(guān)系,已經(jīng)成為抗腫瘤藥物研究的一個新靶點,PTPs抑制劑研究也逐漸成為抗腫瘤藥物發(fā)展的一個新方向。目前,關(guān)于PTPs金屬配合物抑制劑的研究主要集中在釩、銅、鋅等配合物上,然而針對靶向PTPs的鉑配合物抗腫瘤藥物研究在國內(nèi)外還是空白�？紤]到鉑類化合物在惡性腫瘤的化學(xué)治療中占據(jù)著重要地位,以及近期研究發(fā)現(xiàn)鉑配合物也可能通過作用某些蛋白抑制腫瘤細(xì)胞的生長、繁殖現(xiàn)象。本論文以PTPs為靶點,設(shè)計、合成并表征了一系列新型多核鉑類配合物,并且研究了該類配合物與順鉑等臨床藥物對PTPs活性的抑制作用及機理,主要研究內(nèi)容和結(jié)果如下：1.研究了臨床上公認(rèn)的鉑類藥物(如順鉑、卡鉑和奧沙利鉑等)在體外對PTPs活性的抑制作用,結(jié)果表明,順鉑對PTPIB、TCPTP活性的抑制效果最好,而且其對PTPIB抑制的IC50值為TCPTP抑制的10倍,具有很好的選擇性,同時細(xì)胞實驗也表明,順鉑可以有效抑制腫瘤細(xì)胞內(nèi)的PTPs活性。進一步的機理研究表明順鉑能夠以非競爭模式抑制PTPIB,二者的鍵合比為1：1,該研究結(jié)果表明順鉑可能有一個新的抗腫瘤作用機理。2.合成表征了四個三唑席夫堿配體及其對應(yīng)的雙核鉑配合物,成功獲得到三個配合物晶體,研究了該類配合物對PTPs活性的抑制作用,結(jié)果表明配合物對PTPIB和TCPTP活性有一定的抑制作用,但其抑制能力弱于順鉑,熒光滴定實驗顯示其可能作用于PTP1B的活性位點。3.分析各個鉑配合物結(jié)構(gòu)與其活性之間的關(guān)系可以發(fā)現(xiàn),與鉑離子配位的離去基團的存在有利于提高鉑配合物對PTPs活性的抑制能力,同時鉑配合物的空間結(jié)構(gòu)也會影響其抑制能力。這些結(jié)果為我們后續(xù)設(shè)計合成靶向PTPs抗腫瘤鉑配合物提供了理論指導(dǎo)。
[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.
【學(xué)位授予單位】：山西大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R91;O641.4;R96
本文編號：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.
【學(xué)位授予單位】：山西大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R91;O641.4;R96
【共引文獻】
相關(guān)期刊論文 前1條
1 趙娟;尚文斌;于希忠;;Sirt1及其相關(guān)信號通路蛋白調(diào)節(jié)胰島素敏感性的研究進展[J];生命科學(xué)研究;2014年04期
相關(guān)博士學(xué)位論文 前1條
1 宋丹丹;蛋白酪氨酸磷酸酶1B抑制成脂并介導(dǎo)TNFα在肥胖中的作用[D];第二軍醫(yī)大學(xué);2013年
相關(guān)碩士學(xué)位論文 前5條
1 李晨;代謝調(diào)控因子SIRT1基因多態(tài)性與2型糖尿病早期腎病的關(guān)聯(lián)研究[D];青島大學(xué);2014年
2 黃立偉;化合物CXW增強細(xì)胞胰島素反應(yīng)性及其作用機制的實驗研究[D];北京協(xié)和醫(yī)學(xué)院;2014年
3 李寧;超聲輔助提取青莢葉多酚工藝及抗氧化活性的研究[D];鄭州大學(xué);2014年
4 趙曉燕;老年癡呆病理與SUMO-1修飾的相關(guān)研究[D];復(fù)旦大學(xué);2012年
5 徐斌強;肥胖患者精子蛋白酪氨酸磷酸酶1B異常高表達對精子頂體反應(yīng)的影響[D];南京大學(xué);2013年
，本文編號：2426690
本文鏈接：http://sikaile.net/yixuelunwen/yiyaoxuelunwen/2426690.html
最近更新
教材專著
