本文選題：EGFR酪氨酸激酶 + EGFR抑制劑　； 參考：《北京工業(yè)大學》2016年博士論文

【摘要】：癌癥是危害人類健康的重大疾病。近幾十年來,各國研究者都在致力于開發(fā)高效、低毒的癌癥治療藥物。研究表明,多種癌癥有EGFR過度表達的現(xiàn)象,如非小細胞肺癌、乳腺癌、頭頸癌等。EGFR過度表達引起下游信號的異常激活與腫瘤細胞的增殖、轉(zhuǎn)移、分化、凋亡等密切相關。由于EGFR在癌癥的形成中扮演及其重要的角色,EGFR已經(jīng)成為癌癥靶向治療的重要靶標。以EGFR為靶標開發(fā)的上市藥物Gefitinib及Erlotinib對非小細胞肺癌具有較好的療效,但癌細胞對Gefitinib和Erlotinib已經(jīng)表現(xiàn)出耐藥性,尤其是T790M突變引起的耐藥性。本論文綜合分析了上市或處于臨床的EGFR抑制劑最新研究成果,根據(jù)抑制劑的構(gòu)效關系及EGFR/抑制劑復合物晶體結(jié)構(gòu),選擇喹唑啉為母核進行EGFR酪氨酸激酶抑制劑的設計與合成,共合成了87個目標化合物,并測定和分析了這些化合物的生物活性。首先,設計、合成了一系列喹唑啉并二氧六元環(huán)的衍生物。大部分的目標化合物表現(xiàn)了中等到顯著的EGFRwt及EGFRT790M/L858R激酶抑制活性,其中21個化合物對EGFRwt激酶抑制活性小于50 n M,11個化合物對EGFRT790M/L858R突變激酶抑制活性小于100 n M�；衔颪-(3-氯-4-氟苯基)-5-乙氧基-2,3-二氫-[1,4]二VA烷[2,3-f]喹唑啉-10-胺(29b1)具有最顯著的EGFRwt(IC50=2.0 n M)及EGFRT790M/L858R(IC50=6.9 n M)激酶抑制活性。對激酶有顯著抑制活性的化合物對腫瘤細胞H358及A549的增殖抑制能力也較強。另外,與對照藥相比,大部分化合物對T293細胞毒性較低�；谏鲜鲅芯砍晒�,為探討喹唑啉并六元氧雜環(huán)母核中六元氧雜環(huán)上取代基對生物活性的影響,設計并合成了一系列2,3-二氫-[1,4]二VA英[2,3-f]喹唑啉-10-胺衍生物,并評價這些化合物的EGFR激酶抑制活性。實驗結(jié)果表明,所合成的22個目標化合物都有較好的抑制活性(10.29 n M≤IC50≤652.3 n M),其中化合物47b、47c、48b及48c對EGFRwt的抑制活性與對照藥Gefitinib和Erlotinib相近,對激酶有顯著抑制活性的化合物對NCI-H157腫瘤細胞的增殖也表現(xiàn)較強的抑制作用。與對照藥相比,大部分化合物對T293細胞毒性較低。為進一步探討母核結(jié)構(gòu)與生物活性的關系,我們設計并合成了一系列嗎啉酮并喹唑啉類衍生物,這些化合物大部分對EGFRwt激酶表現(xiàn)了較強的抑制活性。21個目標化合物中,19個的IC50值在53 n M到830 n M之間,其中4-(3-氯-4-氟苯基氨基)-6-(3-嗎啉丙基)-6H-[1,4]惡嗪[3,2-g]喹唑啉-7(8H)-酮(60a8)顯示出良好的的抑制效果,其IC50值為53.1 n M。對60a7與60a8進一步的生物活性研究表明,兩個化合物對L858R/T790M突變的EGFR有較好的抑制作用。與對照藥Gefitinib與Erlotinib相比,兩個化合物對H358及A549細胞顯示較強的增殖抑制作用。選取81個目標化合物進行三維定量構(gòu)效關系研究,對29a2進行分子動力學模擬,結(jié)果合理解釋化合物的構(gòu)效關系,為進一步結(jié)構(gòu)優(yōu)化,發(fā)現(xiàn)新型EGFR酪氨酸激酶抑制劑提供了基礎。
[Abstract]:Cancer is a major disease that endangers human health. In recent decades, researchers around the world have been working to develop effective, low-toxic cancer treatment drugs. Studies have shown that overexpression of EGFR in many cancers, such as non-small cell lung cancer, breast cancer, head and neck cancer, etc., leads to abnormal activation of downstream signal, which is closely related to proliferation, metastasis, differentiation and apoptosis of tumor cells. EGFR has become an important target of cancer targeted therapy because it plays an important role in the development of cancer. Gefitinib and Erlotinib, which are targeted at EGFR, have a good effect on non-small cell lung cancer, but the cancer cells have shown resistance to Gefitinib and Erlotinib, especially the resistance caused by T790M mutation. In this paper, the latest research results of EGFR inhibitors on the market or in clinic were analyzed. According to the structure activity relationship of the inhibitors and the crystal structure of EGFR/ inhibitor complexes, quinazoline was selected as mother nucleus to design and synthesize EGFR tyrosine kinase inhibitors. A total of 87 target compounds were synthesized and their biological activities were determined and analyzed. First of all, a series of derivatives of quinazoline dioxide-hexagonal ring were designed and synthesized. Most of the target compounds showed moderate to significant inhibitory activities of EGFRwt and EGFRT790M/L858R kinases, of which 21 showed inhibitory activities against EGFRwt kinases less than 50 nm, and 11 compounds showed inhibitory activities against EGFRT790M/L858R mutant kinases less than 100nM. The compound N-O3-Chloro-4-fluorophenyl-5-ethoxyl-3-dihydro- [1t4] divalane [2n- f] quinazoline-10-amine 29b1) has the most significant inhibitory activity of EGFRwt(IC50=2.0 n M) and EGFRT790M/L858R(IC50=6.9 n M) kinase. Compounds with significant inhibitory activity to kinase also had strong inhibitory effect on proliferation of tumor cells H358 and A549. In addition, most of the compounds were less toxic to T293 cells than the control drugs. Based on the above results, in order to investigate the effect of substituents on the biological activity of hexaoxane heterocyclic heterocyclic compounds in quinazoline, a series of derivatives of 2O3-dihydro- [1O4] di-VA [2O3-f] quinazoline-10-amine were designed and synthesized. The inhibitory activity of EGFR kinase was evaluated. The results showed that all of the 22 target compounds had good inhibitory activity (10.29nM 鈮，

本文編號：1799134