本文關(guān)鍵詞： 表觀遺傳學(xué) 組蛋白去乙�；� 抗腫瘤 靛紅 鄰苯二胺　出處：《山東大學(xué)》2017年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：腫瘤作為嚴(yán)重影響人類(lèi)健康的疾病,近年來(lái)其發(fā)病率和死亡率有著愈演愈烈的趨勢(shì)。開(kāi)發(fā)腫瘤治療的新方法和新藥物,提高腫瘤治療的治愈率成為如今全球生物醫(yī)藥領(lǐng)域研究機(jī)構(gòu)和研發(fā)人員最為關(guān)注的焦點(diǎn)之一。近幾十年興起的表觀遺傳學(xué),為腫瘤疾病的發(fā)病機(jī)理和相關(guān)治療提供了全新的思維和機(jī)遇。表觀遺傳學(xué)家認(rèn)為,腫瘤的發(fā)病不僅與基因突變有關(guān),而且也涉及到表觀遺傳學(xué)調(diào)控。組蛋白乙�；腿ヒ阴；降膭�(dòng)態(tài)變化是由組蛋白乙酰基轉(zhuǎn)移酶(histone acetyltransferases,HATs)和組蛋白去乙�；�(histone deacetylases,HDACs)調(diào)控的,這是一種典型的表觀遺傳學(xué)事件。簡(jiǎn)言之,當(dāng)腫瘤細(xì)胞內(nèi)HDACs表達(dá)增多,組蛋白處于低乙酰化狀態(tài),此時(shí)正電性組蛋白與負(fù)電性DNA緊密結(jié)合,使轉(zhuǎn)錄因子或協(xié)同轉(zhuǎn)錄因子與DNA啟動(dòng)子區(qū)域結(jié)合受到影響,抑制基因轉(zhuǎn)錄。HATs的作用與之相反。目前共發(fā)現(xiàn)18個(gè)人源性HDAC亞型,根據(jù)它們與酵母菌細(xì)胞HDACs的同源性,分成class Ⅰ-Ⅳ四個(gè)亞族。每一個(gè)HDAC亞型都有各自的生物學(xué)功能,而且?guī)缀趺恳粋�(gè)亞型都與癌癥的發(fā)生和發(fā)展相關(guān),所以HDACs成為新型抗腫瘤藥物的設(shè)計(jì)和研發(fā)的新靶點(diǎn)。已經(jīng)有5個(gè)HDAC抑制劑(HDACIs)作為抗腫瘤藥物,獲得U.S.FDA(美國(guó)食品藥品監(jiān)督管理局)或CFDA(中國(guó)食品藥品監(jiān)督管理局)的上市批準(zhǔn)。另有20多個(gè)HDACIs處于不同臨床階段,其中以廣譜HDACIs為主。在本實(shí)驗(yàn)室前期的工作中,將具有多種生物學(xué)功能的內(nèi)源性物質(zhì)靛紅(isatin)作為基本骨架設(shè)計(jì)并合成了一系列具有良好抗腫瘤活性的廣譜HDACIs。本論文在此基礎(chǔ)上,通過(guò)骨架躍遷和拼合原理對(duì)先導(dǎo)化合物9a進(jìn)行結(jié)構(gòu)優(yōu)化,希望得到一系列對(duì)HDACs抑制活性好、選擇性高、抗腫瘤效果理想的新型HDACIs。經(jīng)過(guò)化學(xué)合成手段,我們最終得到了一系列以靛紅衍生結(jié)構(gòu)作為cap區(qū)、鄰苯二胺作為ZBG基團(tuán)的新型HDACIs。進(jìn)一步的生物活性評(píng)價(jià)研究發(fā)現(xiàn),這部分化合物大都具有良好的HDACs抑制活性,而且化合物9m和9n顯示出比陽(yáng)性藥entinostat(MS-275)更好的HDACs抑制活性和與它相似的抑制腫瘤細(xì)胞增殖活性。其中,化合物23a具有高度的HDAC1/2雙選擇性。另外,值得注意的是化合物9n表現(xiàn)出了一定程度的HDAC1亞型選擇性。本論文為新型亞型選擇性HDACIs,尤其是HDAC1選擇性抑制劑的研究奠定了基礎(chǔ)。
[Abstract]:Cancer as a serious disease affecting human health in recent years has a growing trend of morbidity and mortality. The development of new methods and new drugs for cancer treatment. Improving the cure rate of cancer treatment has become one of the most important concerns of researchers and researchers in the field of biomedicine worldwide. Epigenetics has emerged in recent decades. It provides a new way of thinking and opportunity for the pathogenesis and treatment of tumor diseases. Epigeneticists believe that the pathogenesis of cancer is not only related to gene mutation. It also involves epigenetic regulation. The dynamic changes in histone acetylation and deacetylation levels are caused by histone acetyltransferase (histone acetyltransferase). Histone acetyltransferases. HATs) and histone deacetylasesus (HDACs), a typical epigenetic event. When the expression of HDACs in tumor cells increased and histone was in a low acetylation state, the positive electrical histone was closely bound to negatively charged DNA. The binding of transcription factor or co-transcription factor to DNA promoter region was affected, and the inhibitory effect of gene transcription. HATs was opposite. A total of 18 individual HDAC subtypes were found. According to their homology with HDACs of yeast cells, they were divided into four subfamilies of class 鈪，

本文編號(hào)：1446529