含氧雜環(huán)的噻唑—吡唑類(lèi)衍生物設(shè)計(jì)、修飾與生物活性評(píng)價(jià)
發(fā)布時(shí)間：2018-11-26 11:29
【摘要】：癌癥是一種多因素誘導(dǎo)的疾病,近年來(lái),各種癌癥的發(fā)病率越來(lái)越高,對(duì)人類(lèi)健康的威脅也越來(lái)越大。因此,對(duì)新型抗腫瘤化合物的研究引起人們?cè)絹?lái)越多的關(guān)注。受體酪氨酸激酶(RTKs)和表皮生長(zhǎng)因子受體(EGFR)在調(diào)節(jié)腫瘤細(xì)胞增殖,分化,存活和凋亡中扮演非常重要的角色。配體與EGFR結(jié)合后,受體發(fā)生二聚化而發(fā)揮作用。EGFR和HER-2是目前腫瘤研究中最熱門(mén)的靶點(diǎn),因?yàn)樗鼈兊倪^(guò)度表達(dá)或異�；罨Ｒ鸺�(xì)胞惡性增生。吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)是這類(lèi)藥物的代表,可以抑制EGFR/HER-2的過(guò)度表達(dá),已經(jīng)被美國(guó)食品藥品監(jiān)督管理局批準(zhǔn)用來(lái)治療非小細(xì)胞肺癌。很多具有吡唑骨架的化合物具有抗腫瘤、抗菌、抗炎癥等多種生物活性,它們?cè)诨瘜W(xué)界、醫(yī)學(xué)界及藥學(xué)界引起了人們的廣泛關(guān)注。噻唑環(huán)衍生物也具有廣譜的生物活性,如抗結(jié)核、抗菌、抗腫瘤等活性。尤其在與某些特定的活性基團(tuán)結(jié)合后,吡唑和噻唑環(huán)能表現(xiàn)出更強(qiáng)的生物活性,這些特定的結(jié)構(gòu)基團(tuán)包括苯環(huán),含氧雜環(huán)或者一些單鏈結(jié)構(gòu),如酰胺、磺酰脲等等。本論文設(shè)計(jì)合成了一系列具有噻唑和吡唑骨架衍生物的新型化合物,并進(jìn)行了系統(tǒng)的活性篩選和構(gòu)效關(guān)系研究,其中多數(shù)化合物具有很好的EGFR和HER-2抑制活性。根據(jù)基于結(jié)構(gòu)設(shè)計(jì)的原理,借助于分子模擬計(jì)算技術(shù),共設(shè)計(jì)合成了20個(gè)新化合物,并測(cè)試了所有化合物的生物活性,簡(jiǎn)述如下：合成了20個(gè)含氧雜環(huán)的噻唑-吡唑衍生物(C1-C20),并測(cè)定了它們的EGFR和HER-2抑制活性。首先分四步進(jìn)行化學(xué)合成。然后對(duì)所有化合物進(jìn)行結(jié)構(gòu)鑒定,包括1H NMR、ESI-MS以及元素分析。最后對(duì)本系列化合物進(jìn)行活性測(cè)定,主要包括MCF-7和B16-F10增殖試驗(yàn),Western blotting, HER-2抑制試驗(yàn)。分子模擬結(jié)果顯示,HER-2的ATP作用位點(diǎn)的氨基酸殘基與化合物C6之間結(jié)合的最好(形成2個(gè)氫鍵)。綜合分子模擬和生物活性篩選的結(jié)果,我們發(fā)現(xiàn)化合物C6對(duì)HER-2的抑制活性最好,ICso值為0.18 μM,與陽(yáng)性對(duì)照Erlotinib相當(dāng)。
[Abstract]:Cancer is a multi-factor induced disease. In recent years, the incidence of various cancers is increasing, and the threat to human health is also increasing. Therefore, more and more attention has been paid to the study of new anti-tumor compounds. Receptor tyrosine kinase (RTKs) and epidermal growth factor receptor (EGFR) play important roles in regulating proliferation, differentiation, survival and apoptosis of tumor cells. EGFR and HER-2 are the most popular targets in tumor research at present because their overexpression or abnormal activation often cause malignant proliferation of cells. Gefitinib (Gefitinib) and erlotinib (Erlotinib) are such drugs that inhibit the overexpression of EGFR/HER-2 and have been approved by the Food and Drug Administration for the treatment of non-small cell lung cancer. Many compounds with pyrazole skeleton have many biological activities, such as antitumor, antimicrobial, anti-inflammatory and so on, which have attracted wide attention in chemical, medical and pharmaceutical fields. Thiazole ring derivatives also have broad-spectrum biological activities, such as anti-tuberculosis, anti-bacterial, anti-tumor activities. Especially after binding with certain active groups, pyrazole and thiazole can exhibit stronger biological activity. These specific structural groups include benzene ring, oxygen-containing heterocyclic or some single-stranded structures, such as amide, sulfonylurea and so on. In this paper, a series of novel compounds with thiazole and pyrazole derivatives were designed and synthesized, and their activity screening and structure-activity relationship were systematically studied. Most of the compounds had good EGFR and HER-2 inhibitory activities. Based on the principle of structural design, a total of 20 new compounds were designed and synthesized with the help of molecular simulation techniques, and the biological activities of all compounds were tested. Twenty thiazole-pyrazole derivatives (C1-C20) containing oxygen heterocyclic compounds were synthesized and their EGFR and HER-2 inhibitory activities were determined. First, chemical synthesis is carried out in four steps. Then all the compounds were identified, including 1H NMR,ESI-MS and elemental analysis. Finally, the activity of this series of compounds was determined, including MCF-7 and B16-F10 proliferation test, Western blotting, HER-2 inhibition test. The results of molecular simulation showed that the amino acid residues at the ATP interaction site of HER-2 had the best binding to compound C 6 (forming two hydrogen bonds). Based on the results of molecular simulation and bioactivity screening, we found that the inhibitory activity of compound C6 on HER-2 was the best, with a ICso value of 0.18 渭 m, which was comparable to that of the positive control Erlotinib.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R91
本文編號(hào)：2358437
[Abstract]:Cancer is a multi-factor induced disease. In recent years, the incidence of various cancers is increasing, and the threat to human health is also increasing. Therefore, more and more attention has been paid to the study of new anti-tumor compounds. Receptor tyrosine kinase (RTKs) and epidermal growth factor receptor (EGFR) play important roles in regulating proliferation, differentiation, survival and apoptosis of tumor cells. EGFR and HER-2 are the most popular targets in tumor research at present because their overexpression or abnormal activation often cause malignant proliferation of cells. Gefitinib (Gefitinib) and erlotinib (Erlotinib) are such drugs that inhibit the overexpression of EGFR/HER-2 and have been approved by the Food and Drug Administration for the treatment of non-small cell lung cancer. Many compounds with pyrazole skeleton have many biological activities, such as antitumor, antimicrobial, anti-inflammatory and so on, which have attracted wide attention in chemical, medical and pharmaceutical fields. Thiazole ring derivatives also have broad-spectrum biological activities, such as anti-tuberculosis, anti-bacterial, anti-tumor activities. Especially after binding with certain active groups, pyrazole and thiazole can exhibit stronger biological activity. These specific structural groups include benzene ring, oxygen-containing heterocyclic or some single-stranded structures, such as amide, sulfonylurea and so on. In this paper, a series of novel compounds with thiazole and pyrazole derivatives were designed and synthesized, and their activity screening and structure-activity relationship were systematically studied. Most of the compounds had good EGFR and HER-2 inhibitory activities. Based on the principle of structural design, a total of 20 new compounds were designed and synthesized with the help of molecular simulation techniques, and the biological activities of all compounds were tested. Twenty thiazole-pyrazole derivatives (C1-C20) containing oxygen heterocyclic compounds were synthesized and their EGFR and HER-2 inhibitory activities were determined. First, chemical synthesis is carried out in four steps. Then all the compounds were identified, including 1H NMR,ESI-MS and elemental analysis. Finally, the activity of this series of compounds was determined, including MCF-7 and B16-F10 proliferation test, Western blotting, HER-2 inhibition test. The results of molecular simulation showed that the amino acid residues at the ATP interaction site of HER-2 had the best binding to compound C 6 (forming two hydrogen bonds). Based on the results of molecular simulation and bioactivity screening, we found that the inhibitory activity of compound C6 on HER-2 was the best, with a ICso value of 0.18 渭 m, which was comparable to that of the positive control Erlotinib.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R91
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