稀土—全反式维甲酸—氨基酸三元配合物的合成、表征及抗肿瘤活性研究

发布时间：2018-09-10 21:38

【摘要】：癌症一直严重威胁着人们的健康，也是全球疾病治疗方面的主要负担。人类与肿瘤疾病的对抗史可以追溯到2000年前，近50年来，随着医学研究的进步，人们对肿瘤的认识有了根本的改变，，对肿瘤的防治成为各界人士关注的焦点。对于无机药物研究者，一个重要的挑战是怎样较好的平衡金属配合物的药理活性和潜在的毒性，进而实现对金属配合物的合理设计。为进一步研究稀土配合物作为药物使用方面的应用，本论文报道了稀土离子(Nd3+、Eu3+、La3+、Sc3+)-全反式维甲酸-氨基酸(L-精氨酸、L-缬氨酸、L-谷氨酸)三元配合物的合成、表征和其抗肿瘤活性进行体外实验的研究结果。结果表明，配合物的抗肿瘤活性基本强于配体全反式维甲酸、三种相应的氨基酸和金属硝酸盐，稀土配合物对三种癌细胞株(HepG2A549Hela)生长的抑制作用基本上随配合物浓度的增大而增强。通过荧光,黏度法等研究了配合物与药物靶分子DNA的相互作用，结果表明配合物与DNA以嵌入的方式相互作用，推测配合物抗肿瘤活性的起效与这种嵌入DNA双螺旋结构的作用方式有关。本论文的研究工作为设计合成高效低毒的稀土抗肿瘤药物提供了一定的思路和实验依据。本论文分为以下五部分： 1.综述了抗肿瘤药物的研究进展。重点叙述了金属及其配合物、维甲酸、氨基酸和稀土元素的结构特点、性质、生理活性及其在抗肿瘤方面的研究现状；介绍了金属与DNA相互作用的模式，抗肿瘤药物筛选常用的方法。 2.合成了稀土离子(Nd3+、Eu3+、La3+、Sc3+)-全反式维甲酸-L-精氨酸盐酸盐四种新型的三元配合物，利用元素分析、红外光谱、热重分析和紫外光谱对配合物进行了表征，并利用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)测试方法，初步探讨了配合物对体外培养的人肝癌细胞HepG2、人肺癌细胞A549和人宫颈癌细胞Hela生长的影响。采取光谱和黏度法探究了配合物与ct-DNA的作用模式。实验结果表明，ScL2L'Cl配合物有较大的潜在药物使用价值。 3.合成了稀土离子(Nd3+、Eu3+、La3+、Sc3+)-全反式维甲酸-L-缬氨酸四种新型的三元配合物，利用元素分析、红外光谱、热重分析和紫外光谱对配合物进行了表征，并利用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)测试方法，初步探讨了配合物对体外培养的人肝癌细胞HepG2、人肺癌细胞A549和人宫颈癌细胞Hela生长的影响。采取光谱和黏度法探究了配合物与ct-DNA的作用模式。实验结果表明，EuL2L'和ScL2L'配合物在抗肿瘤药物的研发上有较好的研究前景。 4.合成了稀土离子(Nd3+、Eu3+、La3+、Sc3+)-全反式维甲酸-L-谷氨酸四种新型的三元配合物，利用元素分析、红外光谱、热重分析和紫外光谱对配合物进行了表征，并利用3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)测试方法，初步探讨了配合物对体外培养的人肝癌细胞HepG2、人肺癌细胞A549和人宫颈癌细胞Hela生长的影响。采取光谱和黏度法探究了配合物与ct-DNA的作用模式。实验结果表明，EuL2L'是一种潜在的抗癌药物，需要做更深入的研究来确定它的药用价值。 5.报道了四种稀土氧化物(Nd2O3、Eu2O3、La2O3、Sc2O3)对人肝癌细胞HepG2的抗肿瘤活性进行体外实验的研究结果，进一步从稀土离子的角度总结了稀土三元配合物对人肝癌细胞HepG2、人肺癌细胞A549和人宫颈癌细胞Hela三株肿瘤细胞增殖的抑制作用的变化趋势，以期在抗肿瘤药物研究方面提供一定的实验依据。
[Abstract]:Cancer has been a serious threat to people's health and a major burden on the treatment of diseases worldwide. The history of the fight against cancer can be traced back to 2000 years ago. In the past 50 years, with the progress of medical research, people's understanding of cancer has changed fundamentally. The prevention and treatment of cancer has become the focus of attention of people from all walks of life. An important challenge for drug researchers is how to balance the pharmacological activity and potential toxicity of metal complexes to achieve a rational design of metal complexes.
In order to further study the application of rare earth complexes as drugs, the synthesis, characterization and antitumor activity of ternary complexes of rare earth ions (Nd3 +, Eu3 +, La3 +, Sc3 +) - all-trans retinoic acid-amino acid (L-arginine, L-valine, L-glutamic acid) were studied in vitro. The inhibitory effect of three amino acids, metal nitrates and rare earth complexes on the growth of three cancer cell lines (HepG2? A549? Hela) was enhanced with the increase of the concentration of the complexes. The interaction between the complexes and the target DNA was studied by fluorescence and viscosity methods. It is suggested that the interaction between the complexes and DNA is in the way of embedding, and the anticancer activity of the complexes may be related to the double helix structure of DNA.
This thesis is divided into five parts:
1. The research progress of antitumor drugs is reviewed. The structural characteristics, properties, physiological activities and antitumor research status of metals and their complexes, retinoic acid, amino acids and rare earth elements are described in detail.
2. Four new ternary complexes of rare earth ions (Nd3 +, Eu3 +, La3 +, Sc3 +) with all-trans retinoic acid-L-arginine hydrochloride were synthesized. The complexes were characterized by elemental analysis, infrared spectroscopy, thermogravimetric analysis and ultraviolet spectroscopy, and were tested by 3-(4,5-dimethylthiazole-2) -2,5-diphenyltetrazolium bromide (MTT). The effect of the complex on the growth of human hepatoma cell HepG2, human lung cancer cell A549 and human cervical cancer cell Hela in vitro was studied by spectroscopy and viscosity method.
3. Four new ternary complexes of rare earth ions (Nd3 +, Eu3 +, La3 +, Sc3 +) - all-trans retinoic acid-L-valine were synthesized. The complexes were characterized by elemental analysis, infrared spectroscopy, thermogravimetric analysis and ultraviolet spectroscopy. The complexes were characterized by 3-(4,5-dimethylthiazole-2) -2,5-diphenyltetrazolium bromide (MTT) method. The effects of EuL2L'and SCL2L' complexes on the growth of human hepatoma cell HepG2, human lung cancer cell A549 and human cervical cancer cell Hela were studied by spectroscopy and viscosity method.
4. Four new ternary complexes of rare earth ions (Nd3 +, Eu3 +, La3 +, Sc3 +) - all-trans retinoic acid-L-glutamic acid were synthesized. The complexes were characterized by elemental analysis, infrared spectroscopy, thermogravimetric analysis and ultraviolet spectroscopy. The complexes were characterized by 3-(4,5-dimethylthiazole-2) -2,5-diphenyltetrazolium bromide (MTT) method. The effects of EuL2L'on the growth of human hepatoma cell HepG2, human lung cancer cell A549 and human cervical cancer cell Hela were studied by spectroscopy and viscosity method.
5. The antitumor activity of four rare earth oxides (Nd2O3, Eu2O3, La2O3, Sc2O3) on human hepatoma cell line HepG2 in vitro was studied. The inhibitory effects of rare earth ternary complexes on the proliferation of human hepatoma cell HepG2, human lung cancer cell A549 and human cervical cancer cell Hela were summarized from the perspective of rare earth ions. In order to provide some experimental evidence for the research of antineoplastic agents.
【学位授予单位】：西北师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.3;O627.3

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