本文選題：HDAC　切入點(diǎn)：腫瘤成像　出處：《華東師范大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：近年來,癌癥的發(fā)病率、死亡率仍在不斷上升,它仍是難以攻克的世界難題。組蛋白去乙�；窰DAC在多種癌細(xì)胞中高表達(dá),它在基因轉(zhuǎn)錄、功能性蛋白調(diào)控方面發(fā)揮著重要作用,是現(xiàn)在癌癥診斷、治療的一個(gè)重要靶標(biāo)。本論文利用HDAC在腫瘤細(xì)胞中的關(guān)鍵作用,設(shè)計(jì)合成了一個(gè)新型的HDAC近紅外熒光探針。本論文根據(jù)最近研究報(bào)道的湖大染料,利用其優(yōu)異的光學(xué)性質(zhì)對(duì)其進(jìn)行結(jié)構(gòu)改造。在不影響光學(xué)性質(zhì)的前提下,引入HDAC抑制劑SAHA的藥效團(tuán)結(jié)構(gòu),增添HDAC靶向性,設(shè)計(jì)合成了一個(gè)新型的HDAC近紅外熒光探針。為了驗(yàn)證它的靶向性,我們又合成一個(gè)具有相同光學(xué)特性但無HDAC靶向性的近紅外染料與之對(duì)照。首先通過實(shí)驗(yàn)驗(yàn)證了探針的體外以及細(xì)胞水平上HDAC的抑制活性。MDA-MB-231細(xì)胞以及HeLa細(xì)胞株的HDAC高表達(dá),為此我們選用這兩種細(xì)胞進(jìn)行了一系列生物實(shí)驗(yàn),細(xì)胞毒性實(shí)驗(yàn)和熒光成像實(shí)驗(yàn)。在細(xì)胞毒性實(shí)驗(yàn)中,探針在HeLa細(xì)胞中表現(xiàn)出中等強(qiáng)度的細(xì)胞毒;在細(xì)胞成像實(shí)驗(yàn)中,通過兩個(gè)化合物作用后細(xì)胞熒光強(qiáng)度的比較,進(jìn)一步驗(yàn)證了探針的HDAC靶向性與胞內(nèi)滯留的特點(diǎn)。本論文設(shè)計(jì)合成的近紅外熒光探H-A具有良好的光學(xué)性質(zhì),可以很好的靶向胞內(nèi)的組蛋白去乙�；�,可用于HDAC抑制藥物的篩選。在生物實(shí)驗(yàn)中發(fā)現(xiàn)的HDAC抑制劑胞內(nèi)滯留的特點(diǎn),可用于設(shè)計(jì)具有HDAC靶向性的傳統(tǒng)抗腫瘤藥物的前藥。
[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.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914
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本文編號(hào)：1564217