基于组蛋白去乙酰化酶（HDAC）的近红外荧光探针的设计与合成

发布时间：2018-03-04 05:04

  本文选题：HDAC　切入点：肿瘤成像　出处：《华东师范大学》2017年硕士论文　论文类型：学位论文

【摘要】：近年来,癌症的发病率、死亡率仍在不断上升,它仍是难以攻克的世界难题。组蛋白去乙酰化酶HDAC在多种癌细胞中高表达,它在基因转录、功能性蛋白调控方面发挥着重要作用,是现在癌症诊断、治疗的一个重要靶标。本论文利用HDAC在肿瘤细胞中的关键作用,设计合成了一个新型的HDAC近红外荧光探针。本论文根据最近研究报道的湖大染料,利用其优异的光学性质对其进行结构改造。在不影响光学性质的前提下,引入HDAC抑制剂SAHA的药效团结构,增添HDAC靶向性,设计合成了一个新型的HDAC近红外荧光探针。为了验证它的靶向性,我们又合成一个具有相同光学特性但无HDAC靶向性的近红外染料与之对照。首先通过实验验证了探针的体外以及细胞水平上HDAC的抑制活性。MDA-MB-231细胞以及HeLa细胞株的HDAC高表达,为此我们选用这两种细胞进行了一系列生物实验,细胞毒性实验和荧光成像实验。在细胞毒性实验中,探针在HeLa细胞中表现出中等强度的细胞毒;在细胞成像实验中,通过两个化合物作用后细胞荧光强度的比较,进一步验证了探针的HDAC靶向性与胞内滞留的特点。本论文设计合成的近红外荧光探H-A具有良好的光学性质,可以很好的靶向胞内的组蛋白去乙酰化酶,可用于HDAC抑制药物的筛选。在生物实验中发现的HDAC抑制剂胞内滞留的特点,可用于设计具有HDAC靶向性的传统抗肿瘤药物的前药。
[Abstract]:In recent years, the incidence and mortality of cancer is still rising, it is still a difficult problem in the world. Histone deacetylase HDAC is highly expressed in a variety of cancer cells, it is transcribed in genes. Functional protein plays an important role in the regulation of cancer and is an important target for cancer diagnosis and treatment. In this paper, we use the key role of HDAC in tumor cells. A novel HDAC near infrared fluorescence probe was designed and synthesized. In this paper, the structure of the dye was modified by its excellent optical properties. A novel HDAC near infrared fluorescence probe was designed and synthesized by introducing the pharmacophore structure of HDAC inhibitor SAHA and increasing the targeting of HDAC. We also synthesized a near infrared dye with the same optical properties but no HDAC targeting. Firstly, we verified the high expression of HDAC inhibitory activity. MDA-MB-231 cells and HeLa cell lines, both in vitro and at the cell level. So we selected these two kinds of cells to do a series of biological experiments, cytotoxicity test and fluorescence imaging experiment. In the cytotoxicity test, the probe showed moderate cytotoxicity in HeLa cells, and in the cell imaging experiment, By comparing the fluorescence intensity of the two compounds, the characteristics of HDAC targeting and intracellular retention of the probe were further verified. The designed and synthesized near infrared fluorescence detector H-A has good optical properties. It can be used in the screening of HDAC inhibitors. The characteristics of intracellular retention of HDAC inhibitors found in biological experiments can be used to design prodrugs of traditional antitumor drugs with HDAC targeting.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914
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本文编号：1564217