两类二氢吡唑衍生物的合成及生物活性评价

发布时间：2018-04-19 15:08

  本文选题：吡唑衍生物 + 黑色素瘤　； 参考：《南京大学》2014年硕士论文

【摘要】：当今世界,杂环化合物在医药、农药的研究开发中占有十分重要的地位。无论是天然的还是人工合成的杂环化合毗唑物,在医药(抗癌、杀虫、杀菌),都起着非常重要的作用。吡唑衍生物是一类多功能化合物,许多衍生物可以用作杀虫剂、杀菌剂、除草剂、催化剂、抗菌药,具有抗癌、抗肿瘤、抗菌、抗病毒、抗惊厥等多种生物活性,所以一直是人们研究的热点。本文中,通过前期工作中已经合成的含羟基的和含三氟甲苯基的查尔酮衍生物与水合肼反应形成了一系列未经报道的吡唑衍生物类的新化合物。黑色素瘤是一种恶性程度十分高的恶性肿瘤,其致死率极高达80%。研究表明,RAF亚型BRAF激酶是该通路中与黑色素瘤关系最密切的激酶之一,BRAF作为一种原癌基因,8%的癌细胞中发现BRAF基因突变,而在黑色素瘤中突变率达50-70%,其中90%的癌细胞中发现的BRAF基因突变是位于600位的缬氨酸V被谷氨酸E取代(V600E)。该突变导致MAPK通路大大激活,从而导致癌细胞的增殖、生存和转移。近年来基于BRAFV600E激酶为靶点研制了各种抗黑色素瘤靶向抑制剂,其中抑制活性较好的有vemurafenib、dabrafenib等。本课题基于葛兰素史克公司发表的关于SB2590885的研究基础之上,对该化合物进行改造,设计并合成一系列含有羟基的二氢吡唑类化合物,旨在获得较好的BRAFV600E激酶靶向抑制剂。所有化合物进行了BRAFV600E激酶抑制活性和人体黑色素瘤细胞WM226.4株抑制活性的测试,结果所得IC50值均达微摩尔级,其中化合物3d和3m表现出最好的生物活性3d:IC50=O.22μM,3m:IC50=0.46μM,ErlOtinib:IC50 =0.08μM。本课题还对该系列化合物与BRAFV600E激酶进行了计算机模拟分子对接实验,旨在为以后设计更多活性高,毒性小,药效强的BRAFV60OE激酶靶向抑制剂的研究提供理论基础。DNA解旋酶(DNA gyrase)是一个由两个GraA和两个GraB亚基构成的四聚体蛋白,它是DNA拓扑异构酶Ⅱ中的一种亚类,其主要功能为引入负超螺旋,在DNA复制中起十分重要的作用。能抑制DNA解旋酶的相关吡唑衍生物被陆续合成出来,许多DNA解旋酶选择性抑制剂含有芳基吡唑的模板,三氟甲基取代的化合物也被报道具有生物活性并且经常被用来作为杀真菌剂,解热剂和止疼剂。基于此,本课题组设计并合成一系列含有三氟甲苯基的二氢吡唑类化合物,旨在获得较好的DNA解旋酶靶向抑制剂。所有化合物进行了菌株抑制活性的测试,结果所得ICso值均达微摩尔级,其中化合物4d对革兰氏阳性菌具有有效的抑制活性,同时对枯草芽孢杆菌的DNA解旋酶和金黄色葡萄球菌的DNA解旋酶(对枯草芽孢杆菌的DNA解旋酶的IC50=0.125μM,对黄色葡萄球菌DNA解旋酶的IC50=0.125μM)。本课题还对该系列化合物与DNA解旋酶进行了计算机模拟分子对接实验,旨在为以后设计更多活性高,毒性小,药效强的DNA解旋酶靶向抑制剂的研究提供理论基础。
[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，

本文编号：1773595