本文選題：吡唑衍生物 + 黑色素瘤　； 參考：《南京大學(xué)》2014年碩士論文

【摘要】：當(dāng)今世界,雜環(huán)化合物在醫(yī)藥、農(nóng)藥的研究開(kāi)發(fā)中占有十分重要的地位。無(wú)論是天然的還是人工合成的雜環(huán)化合毗唑物,在醫(yī)藥(抗癌、殺蟲(chóng)、殺菌),都起著非常重要的作用。吡唑衍生物是一類(lèi)多功能化合物,許多衍生物可以用作殺蟲(chóng)劑、殺菌劑、除草劑、催化劑、抗菌藥,具有抗癌、抗腫瘤、抗菌、抗病毒、抗驚厥等多種生物活性,所以一直是人們研究的熱點(diǎn)。本文中,通過(guò)前期工作中已經(jīng)合成的含羥基的和含三氟甲苯基的查爾酮衍生物與水合肼反應(yīng)形成了一系列未經(jīng)報(bào)道的吡唑衍生物類(lèi)的新化合物。黑色素瘤是一種惡性程度十分高的惡性腫瘤,其致死率極高達(dá)80%。研究表明,RAF亞型BRAF激酶是該通路中與黑色素瘤關(guān)系最密切的激酶之一,BRAF作為一種原癌基因,8%的癌細(xì)胞中發(fā)現(xiàn)BRAF基因突變,而在黑色素瘤中突變率達(dá)50-70%,其中90%的癌細(xì)胞中發(fā)現(xiàn)的BRAF基因突變是位于600位的纈氨酸V被谷氨酸E取代(V600E)。該突變導(dǎo)致MAPK通路大大激活,從而導(dǎo)致癌細(xì)胞的增殖、生存和轉(zhuǎn)移。近年來(lái)基于BRAFV600E激酶為靶點(diǎn)研制了各種抗黑色素瘤靶向抑制劑,其中抑制活性較好的有vemurafenib、dabrafenib等。本課題基于葛蘭素史克公司發(fā)表的關(guān)于SB2590885的研究基礎(chǔ)之上,對(duì)該化合物進(jìn)行改造,設(shè)計(jì)并合成一系列含有羥基的二氫吡唑類(lèi)化合物,旨在獲得較好的BRAFV600E激酶靶向抑制劑。所有化合物進(jìn)行了BRAFV600E激酶抑制活性和人體黑色素瘤細(xì)胞WM226.4株抑制活性的測(cè)試,結(jié)果所得IC50值均達(dá)微摩爾級(jí),其中化合物3d和3m表現(xiàn)出最好的生物活性3d:IC50=O.22μM,3m:IC50=0.46μM,ErlOtinib:IC50 =0.08μM。本課題還對(duì)該系列化合物與BRAFV600E激酶進(jìn)行了計(jì)算機(jī)模擬分子對(duì)接實(shí)驗(yàn),旨在為以后設(shè)計(jì)更多活性高,毒性小,藥效強(qiáng)的BRAFV60OE激酶靶向抑制劑的研究提供理論基礎(chǔ)。DNA解旋酶(DNA gyrase)是一個(gè)由兩個(gè)GraA和兩個(gè)GraB亞基構(gòu)成的四聚體蛋白,它是DNA拓?fù)洚悩?gòu)酶Ⅱ中的一種亞類(lèi),其主要功能為引入負(fù)超螺旋,在DNA復(fù)制中起十分重要的作用。能抑制DNA解旋酶的相關(guān)吡唑衍生物被陸續(xù)合成出來(lái),許多DNA解旋酶選擇性抑制劑含有芳基吡唑的模板,三氟甲基取代的化合物也被報(bào)道具有生物活性并且經(jīng)常被用來(lái)作為殺真菌劑,解熱劑和止疼劑�；诖�,本課題組設(shè)計(jì)并合成一系列含有三氟甲苯基的二氫吡唑類(lèi)化合物,旨在獲得較好的DNA解旋酶靶向抑制劑。所有化合物進(jìn)行了菌株抑制活性的測(cè)試,結(jié)果所得ICso值均達(dá)微摩爾級(jí),其中化合物4d對(duì)革蘭氏陽(yáng)性菌具有有效的抑制活性,同時(shí)對(duì)枯草芽孢桿菌的DNA解旋酶和金黃色葡萄球菌的DNA解旋酶(對(duì)枯草芽孢桿菌的DNA解旋酶的IC50=0.125μM,對(duì)黃色葡萄球菌DNA解旋酶的IC50=0.125μM)。本課題還對(duì)該系列化合物與DNA解旋酶進(jìn)行了計(jì)算機(jī)模擬分子對(duì)接實(shí)驗(yàn),旨在為以后設(shè)計(jì)更多活性高,毒性小,藥效強(qiáng)的DNA解旋酶靶向抑制劑的研究提供理論基礎(chǔ)。
[Abstract]:In the world, heterocyclic compounds play an important role in the research and development of medicine and pesticides.Both natural and synthetic heterocyclic pyrazole play an important role in medicine (anticancer, insecticidal, bactericidal).Pyrazole derivatives are a class of multifunctional compounds, many of which can be used as insecticides, fungicides, herbicides, catalysts, antimicrobial agents, anticancer, antitumor, antibacterial, antiviral, anticonvulsant and other biological activities.So it has always been the hot spot of people's research.In this paper, a series of unreported pyrazole derivatives have been synthesized by the reaction of hydroxy and trifluorotoluene derivatives with hydrazine hydrate.Melanoma is a malignant tumor with a high degree of malignancy, and its mortality is as high as 80%.It has been shown that BRAF kinase is one of the kinases most closely related to melanoma in this pathway. As a proto-oncogene, BRAF gene mutation is found in 8% of cancer cells.The mutation rate of BRAF gene in melanoma was 50 to 70, 90% of which were found to be valine V at 600 position replaced by glutamate E in 90% of the cancer cells.This mutation leads to a significant activation of the MAPK pathway, leading to the proliferation, survival and metastasis of cancer cells.In recent years, a variety of anti-melanoma targeting inhibitors have been developed based on BRAFV600E kinases, among which vemurafenb dabrafenib has good inhibitory activity.Based on GlaxoSmithKline's research on SB2590885, a series of hydroxy dihydropyrazole compounds were designed and synthesized to obtain better BRAFV600E kinase targeting inhibitors.The inhibitory activity of BRAFV600E kinase and the inhibitory activity of human melanoma cell line WM226.4 were tested. The results showed that the IC50 values of all the compounds reached the level of micro-moles, and the compounds exhibited the best bioactivity, 3d:IC50=O.22 渭 M 渭 MU 3mIC50, 0.46 渭 M-1, ErlOtinib: IC50: IC50, 0.08 渭 M. on the 3rd day, the 3rd day and the 3rd day, the 3 m showed the best bioactivity.In order to design more high activity and less toxicity for the future, the computer simulation molecular docking experiment of this series of compounds with BRAFV600E kinase was also carried out in this paper.BRAFV60OE helicase is a tetramer protein consisting of two GraA and two GraB subunits, which is a subclass of DNA topoisomerase 鈪，

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