抗癌药物及其与DNA相互作用的电化学研究
摘要
众所周知，生命信息传递的物质基础是脱氧核糖核酸(又称DNA)，DNA分子的破坏势必造成生命过程的障碍，甚至中断。因此，对于DNA的研究是目前人们关注的焦点。而肿瘤疾病是造成DNA损伤、威胁人类生命的第一大杀手，自然而然就成了科学界研究的目标。本论文用电化学的方法研究了两种抗癌药物——8-氮鸟嘌呤和6-巯基嘌呤的电化学性质，同时就其与DNA的相互作用也做了初步的探讨。本论文主要内容包括以下几个方面：
1：研究了抗癌药物8-氮鸟嘌呤(8-AG)的示波极谱分析方法。在0.10mol／LH_2SO_4底液中，8-氮鸟嘌呤于-1.03V(vs SCE)产生一灵敏的极谱还原波，峰电流与8-氮鸟嘌呤浓度在1.00×10~(-8)mol／L～9.00×10~(-5)mol／L范围内有良好的线性关系，检测下限达9.00×10~(-9)mol／L。方法操作简便，灵敏度高，准确度好，回收率在95.0％～103％之间。
2：研究了8—氮鸟嘌呤(8-AG)在浸蜡石墨电极上电化学性质。在HAc-NaAc缓冲溶液中，8-AG在浸蜡石墨电极上产生一受扩散控制的氧化波，峰电位为1.20V(vs SCE)，峰电流与8-AG浓度在8.00×10~(-7)mol／L～1.00×10~(-4)mol／L范围内有良好的线性关系，检测下限达5.00×10~(-7)mol／L。电极反应过程利用多种电化学技术进行了详细研究，求得了对应的动力学参数，建立了灵敏、快速的8-AG的检测方法。
3：研究了在HAc-NaAc(pH3.60)缓冲溶液中8—氮鸟嘌呤(8-AG)与双链DNA在浸蜡石墨电极上相互作用的伏安行为。在浸蜡石墨电极上，8-AG在HAc-NaAc(pH3.60)缓冲溶液中有一明显的氧化峰，其峰电位在1.20V(vs SCE)左右，加入双链DNA分子后，二者之间发生静电引力作用，使得8-AG的氧化峰明显地正移；同时随着反应时间、反应温度及DNA加入量的增加，二者作用更加强烈。二者作用90min后，8-AG对正常细胞DNA不再损伤。研究求出对应的动力学参数，建立了定量检测DNA浓度的方法。另外还对8-AG与双链DNA(dsDNA)和单链DNA(ssDNA)作用时产生响应的不同以及其在DNA修饰电极与裸电极上测定的灵敏度进行了比较。
4：采用了多种电化学方法研究了6-巯基嘌呤(6-MP)在悬汞电极上的伏安行为。在磷酸盐缓冲溶液(pH7.40)中，6-MP在悬汞电极上有一对受吸附控制的氧化还原峰，还原峰、氧化峰峰电流与6-MP浓度分别在9.00×10~(-6)mol／l～1.00×10~(-4)mol／L和4.00×10~(-5)～1.00×10~(-4)mol／L范围内有良好的线性关系，检测下限分别为3.00×10~(-7)mol／L和1.00×10~(-7)Tmol／L。由此建立了6-MP电化学分析方法并将该测定方法用于乐疾宁药片中6-MP含量的定量分析及回收率的测定，结果令人满意。
It is well known that Deoxyribonucleic acid (also named DNA) is the transference base of information in the course of life. The destruction of DNA will cause the handicap of life, even discontinuity. So, people focus on the study of DNA. Moreover, cancer is the first killer to cause the destruction of DNA and to threaten human's life. And it becomes the object of the study in the life-science field. In this paper, the Electrochemistry behavior of the anticancer drugs 8-Azaguanine (8-AG) and 6-Mercaptopurine (6-MP) have been studied and the interaction of 8-AG with DNA has been studied too. The main results are expressed as fellows:
1: A new oscillographic polarography method for determination of trace anti-cancer drug 8-azaguanine was investigated. In 0.10mol/L H2SO4 solution, a sensitive reduction peak of 8-azaguanine was obtained with peak potential of -1.03V(vs SCE). The peak currents were linear relationship with 8-azaguanine concentrations in the range of 1.00×10-8mol/L~9.00 10-5mol/L with detection limit of 9.00×10-9mol/L. This method was simple operation and high accuracy. The detect recovery was between 95.0 % and 103 %.
2: The Electrochemistry behavior of the anticancer drug 8-Azaguanine at wax-marinated graphite electrodes had been studied. In the HAc-NaAc(pH3.60) buffer, one oxidation peak of 8-AG,which was diffuse-driven at graphite electrode, was obtained with the peak potential of 1.20V (vs SCE). The peak current was linear relationship with 8-AG concentration in the rang of 1.00×10-8mol/L~9.00×10-5mol/L. The detected limit was up to 9.00×10-9mol/L.The electrode reaction process had been investigated in detail by lots of electrochemistry techniques, and its dynamics parameters had been obtained. Also, the determined methods for 8-AG, which was sensitive and fast has been performed.
3: The interaction of 8-Azaguanine with fish tests double-stranded DNA (dsDNA) and fish tests single-stranded DNA (ssDNA) was studied electrochemically by using differential pulse voltammetry (DPV) and cyclic voltammetry (CV) at wax-marinated graphite electrodes (GE) in a 0.2mol/L acetate buffer (pH3.6). Different effect factors, such as pH, time, temperature, and DNA concentration were investigated. It was observed that the peak current decreased and the peak potential shifted positively with the increasing of time, temperature and DNA concentration respectively. In addition, the peak current was a linear relationship with DNA concentration in the range of 1.00 g/mL ~7.00 g/mL. It was shown that the binding mode between 8-AG and DNA was electro-static interaction. Their electron clouds affected each other and formed a new association of DNA-m8-AG (m=3). Therefore, when 8-AG cures a cancer cell, it damaged a normal cell. Furthermore, The drug 8-AG would not affect the DNA molecule after 90 minutes at room te
mperature. Simultaneously, the electrode reaction process was investigated in detail by some electrochemistry techniques and its dynamics parameters were obtained.
4: The voltrammetry behavior for 6-Mercaptopurine (6-MP) on hanging mercury electrode had been investigated by using some electrochemical methods. In the
phosphate buffer solution (pH7.40), 6-MP showed a pair of redox peak controlled by adsorption. The oxidation peak current and the reduction peak current were a fine linear relationship with the concentration of 6-MP in the range of 9.00×10-6mol/L-1.00×10-4mol/L and 4.00×10-5 -1.00×10-4mol/L respectively with the detection limit of 3.00×10-7mol/L and 1.00×10-7mol/L. At the same time, the quantitative analysis method was also used to determine the quantity of the 6-MP in the tablet of Lejining. Finally, the electrode reaction process had been studied particularly and the kinetic parameters had also been obtained too.
1：研究了抗癌药物8-氮鸟嘌呤(8-AG)的示波极谱分析方法。在0.10mol／LH_2SO_4底液中，8-氮鸟嘌呤于-1.03V(vs SCE)产生一灵敏的极谱还原波，峰电流与8-氮鸟嘌呤浓度在1.00×10~(-8)mol／L～9.00×10~(-5)mol／L范围内有良好的线性关系，检测下限达9.00×10~(-9)mol／L。方法操作简便，灵敏度高，准确度好，回收率在95.0％～103％之间。
2：研究了8—氮鸟嘌呤(8-AG)在浸蜡石墨电极上电化学性质。在HAc-NaAc缓冲溶液中，8-AG在浸蜡石墨电极上产生一受扩散控制的氧化波，峰电位为1.20V(vs SCE)，峰电流与8-AG浓度在8.00×10~(-7)mol／L～1.00×10~(-4)mol／L范围内有良好的线性关系，检测下限达5.00×10~(-7)mol／L。电极反应过程利用多种电化学技术进行了详细研究，求得了对应的动力学参数，建立了灵敏、快速的8-AG的检测方法。
3：研究了在HAc-NaAc(pH3.60)缓冲溶液中8—氮鸟嘌呤(8-AG)与双链DNA在浸蜡石墨电极上相互作用的伏安行为。在浸蜡石墨电极上，8-AG在HAc-NaAc(pH3.60)缓冲溶液中有一明显的氧化峰，其峰电位在1.20V(vs SCE)左右，加入双链DNA分子后，二者之间发生静电引力作用，使得8-AG的氧化峰明显地正移；同时随着反应时间、反应温度及DNA加入量的增加，二者作用更加强烈。二者作用90min后，8-AG对正常细胞DNA不再损伤。研究求出对应的动力学参数，建立了定量检测DNA浓度的方法。另外还对8-AG与双链DNA(dsDNA)和单链DNA(ssDNA)作用时产生响应的不同以及其在DNA修饰电极与裸电极上测定的灵敏度进行了比较。
4：采用了多种电化学方法研究了6-巯基嘌呤(6-MP)在悬汞电极上的伏安行为。在磷酸盐缓冲溶液(pH7.40)中，6-MP在悬汞电极上有一对受吸附控制的氧化还原峰，还原峰、氧化峰峰电流与6-MP浓度分别在9.00×10~(-6)mol／l～1.00×10~(-4)mol／L和4.00×10~(-5)～1.00×10~(-4)mol／L范围内有良好的线性关系，检测下限分别为3.00×10~(-7)mol／L和1.00×10~(-7)Tmol／L。由此建立了6-MP电化学分析方法并将该测定方法用于乐疾宁药片中6-MP含量的定量分析及回收率的测定，结果令人满意。
It is well known that Deoxyribonucleic acid (also named DNA) is the transference base of information in the course of life. The destruction of DNA will cause the handicap of life, even discontinuity. So, people focus on the study of DNA. Moreover, cancer is the first killer to cause the destruction of DNA and to threaten human's life. And it becomes the object of the study in the life-science field. In this paper, the Electrochemistry behavior of the anticancer drugs 8-Azaguanine (8-AG) and 6-Mercaptopurine (6-MP) have been studied and the interaction of 8-AG with DNA has been studied too. The main results are expressed as fellows:
1: A new oscillographic polarography method for determination of trace anti-cancer drug 8-azaguanine was investigated. In 0.10mol/L H2SO4 solution, a sensitive reduction peak of 8-azaguanine was obtained with peak potential of -1.03V(vs SCE). The peak currents were linear relationship with 8-azaguanine concentrations in the range of 1.00×10-8mol/L~9.00 10-5mol/L with detection limit of 9.00×10-9mol/L. This method was simple operation and high accuracy. The detect recovery was between 95.0 % and 103 %.
2: The Electrochemistry behavior of the anticancer drug 8-Azaguanine at wax-marinated graphite electrodes had been studied. In the HAc-NaAc(pH3.60) buffer, one oxidation peak of 8-AG,which was diffuse-driven at graphite electrode, was obtained with the peak potential of 1.20V (vs SCE). The peak current was linear relationship with 8-AG concentration in the rang of 1.00×10-8mol/L~9.00×10-5mol/L. The detected limit was up to 9.00×10-9mol/L.The electrode reaction process had been investigated in detail by lots of electrochemistry techniques, and its dynamics parameters had been obtained. Also, the determined methods for 8-AG, which was sensitive and fast has been performed.
3: The interaction of 8-Azaguanine with fish tests double-stranded DNA (dsDNA) and fish tests single-stranded DNA (ssDNA) was studied electrochemically by using differential pulse voltammetry (DPV) and cyclic voltammetry (CV) at wax-marinated graphite electrodes (GE) in a 0.2mol/L acetate buffer (pH3.6). Different effect factors, such as pH, time, temperature, and DNA concentration were investigated. It was observed that the peak current decreased and the peak potential shifted positively with the increasing of time, temperature and DNA concentration respectively. In addition, the peak current was a linear relationship with DNA concentration in the range of 1.00 g/mL ~7.00 g/mL. It was shown that the binding mode between 8-AG and DNA was electro-static interaction. Their electron clouds affected each other and formed a new association of DNA-m8-AG (m=3). Therefore, when 8-AG cures a cancer cell, it damaged a normal cell. Furthermore, The drug 8-AG would not affect the DNA molecule after 90 minutes at room te
mperature. Simultaneously, the electrode reaction process was investigated in detail by some electrochemistry techniques and its dynamics parameters were obtained.
4: The voltrammetry behavior for 6-Mercaptopurine (6-MP) on hanging mercury electrode had been investigated by using some electrochemical methods. In the
phosphate buffer solution (pH7.40), 6-MP showed a pair of redox peak controlled by adsorption. The oxidation peak current and the reduction peak current were a fine linear relationship with the concentration of 6-MP in the range of 9.00×10-6mol/L-1.00×10-4mol/L and 4.00×10-5 -1.00×10-4mol/L respectively with the detection limit of 3.00×10-7mol/L and 1.00×10-7mol/L. At the same time, the quantitative analysis method was also used to determine the quantity of the 6-MP in the tablet of Lejining. Finally, the electrode reaction process had been studied particularly and the kinetic parameters had also been obtained too.
引文
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