本文選題：組蛋白去乙�；�　切入點：組蛋白去乙�；敢种苿�　出處：《中國海洋大學》2013年碩士論文　論文類型：學位論文

【摘要】：組蛋白去乙�；�(Histone deacetylase,HDACs)是近些年研究較多的腫瘤相關(guān)的分子靶標之一,與腫瘤發(fā)生、發(fā)展和轉(zhuǎn)移以及腫瘤組織的新生血管生成密切相關(guān)。組蛋白去乙�；敢种苿�(Histone deacetylase inhibitors,HDACIs)是以HDACs為靶點而開發(fā)的抗腫瘤藥物,它們能引起細胞周期的阻斷和腫瘤細胞選擇性的凋亡,在體外和動物體內(nèi)都具有明顯抗腫瘤作用。迄今為止,已有兩個HDAC抑制劑(SAHAFK228)被美國食品藥品監(jiān)督管理局(FDA)批準用于治療皮膚T細胞淋巴瘤。因此,開發(fā)高效、低毒、選擇性強的HDAC抑制劑已成為抗腫瘤藥物的重要研究領(lǐng)域之一。MS-275是一種亞型選擇性的HDAC抑制劑,其化學結(jié)構(gòu)為苯甲酰胺類化合物,其口服在動物體內(nèi)具有顯著的抗癌活性且毒性較低,目前該藥物正在美國進行白血病及實體瘤的臨床Ⅱ期研究。本論文以MS-275為先導化合物,根據(jù)現(xiàn)有的同類藥物的構(gòu)效關(guān)系、結(jié)構(gòu)優(yōu)化改造及臨床進展等研究信息,結(jié)合傳統(tǒng)藥物設(shè)計方法設(shè)計合成兩個不同系列的衍生物,以期獲得具有自主知識產(chǎn)權(quán)的系列HDAC抑制劑。設(shè)計的第1類系列化合物是將MS-275的連接鏈進行變換,用脂肪直鏈取代其芳香鏈,酶抑制區(qū)保留了鄰苯二胺的結(jié)構(gòu),表面識別區(qū)用系列(雜)芳基替代MS-275的柔性基團以得到不同的化合物；之后在第1類結(jié)構(gòu)基礎(chǔ)上改造,把Ⅰ類的脂肪直鏈變?yōu)橹经h(huán),以測定環(huán)狀基團對藥物抗腫瘤活性的影響。第Ⅱ類系列化合物用苯磺酰胺取代苯甲酰胺,同樣在表面識別區(qū)用系列(雜)芳基進行替代,同時設(shè)計合成了除苯磺酰胺外與MS-275完全相同的化合物151,以其考察吸電子效應(yīng)更強的磺�；鶊F對于其活性的影響。本文共合成了烷酰胺及苯磺酰胺兩個系列26個新的目標化合物,采用SRB的方法,選擇1株前列腺癌細胞PC3為模型,對第Ⅰ系列化合物的抗腫瘤活性進行初步評價,結(jié)果表明它們并無明顯的抗腫瘤細胞株增殖的能力,推測與連接鏈的芳香基團缺失有關(guān)；同樣選擇前列腺癌細胞PC3為模型,對第Ⅱ系列目標化合物進行初步的活性評價,顯示化合物148和151其具有一定的抑制腫瘤細胞增殖的活性,分子水平的抑制機制的探討正在進行中。本論文為進一步尋找高效低毒的非羥肟酸類HDAC抑制劑提供了一定的研究基礎(chǔ)。
[Abstract]:Histone deacetylase (histone deacetylase HDACs) is one of the molecular targets associated with tumorigenesis in recent years. Histone deacetylase inhibitors (HDACIsa), a histone deacetylase inhibitor, is an antitumor drug developed with HDACs as a target, which can block cell cycle and induce selective apoptosis of tumor cells. To date, two HDAC inhibitors, SAHAFK228, have been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. The highly selective HDAC inhibitors have become one of the important research fields of antitumor drugs. MS-275 is a subtype-selective HDAC inhibitor with the chemical structure of benzoamide compounds. The drug has significant anticancer activity and low toxicity in animals. At present, the drug is currently being studied in the United States for clinical stage II of leukemia and solid tumors. In this paper, MS-275 is used as a lead compound, according to the structure-activity relationship of existing similar drugs. Based on the information of structural optimization and clinical progress, two different series of derivatives were designed and synthesized in combination with traditional drug design methods. In order to obtain a series of HDAC inhibitors with independent intellectual property rights, the first series of compounds were designed to transform the chain of MS-275 to replace its aromatic chain with straight chain of fat, and the inhibitory region of enzyme retained the structure of o-phenylenediamine. The surface recognition zone replaces the flexible groups of MS-275 with a series of (hetero) aryl groups to obtain different compounds, and then transforms the straight chain of type I fat into a fatty ring on the basis of the first type structure. In order to determine the effect of cyclic groups on the antitumor activity of the drug. Class II compounds were substituted by benzamide with benzenesulfonamide and substituted by series (hetero) aryl groups in the surface recognition area. At the same time, the compound 151which is identical to MS-275 except benzenesulfonamide was designed and synthesized. In order to investigate the influence of the more electron-absorbing groups on its activity, 26 series of alkanamide and benzenesulfonamide were synthesized in this paper. New target compounds, Using SRB method, a prostate cancer cell line PC3 was selected as a model to evaluate the antitumor activity of the first series of compounds. The results showed that they had no obvious ability of anti-tumor cell proliferation. The preliminary activity evaluation of the target compounds of the second series showed that compounds 148 and 151had a certain activity of inhibiting the proliferation of tumor cells, which was related to the deletion of aromatic groups in the ligand chain, and the prostate cancer cell line PC3 was also selected as the model to evaluate the activity of the target compounds of the second series. The mechanism of inhibition at molecular level is in progress. This paper provides a basis for further searching for high efficiency and low toxicity non-hydroxamic acid HDAC inhibitors.
【學位授予單位】：中國海洋大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R91;R914.5

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