基于喹唑啉结构的EGFR酪氨酸激酶抑制剂的设计与合成

发布时间：2018-04-25 01:21

  本文选题：EGFR酪氨酸激酶 + EGFR抑制剂　； 参考：《北京工业大学》2016年博士论文

【摘要】：癌症是危害人类健康的重大疾病。近几十年来,各国研究者都在致力于开发高效、低毒的癌症治疗药物。研究表明,多种癌症有EGFR过度表达的现象,如非小细胞肺癌、乳腺癌、头颈癌等。EGFR过度表达引起下游信号的异常激活与肿瘤细胞的增殖、转移、分化、凋亡等密切相关。由于EGFR在癌症的形成中扮演及其重要的角色,EGFR已经成为癌症靶向治疗的重要靶标。以EGFR为靶标开发的上市药物Gefitinib及Erlotinib对非小细胞肺癌具有较好的疗效,但癌细胞对Gefitinib和Erlotinib已经表现出耐药性,尤其是T790M突变引起的耐药性。本论文综合分析了上市或处于临床的EGFR抑制剂最新研究成果,根据抑制剂的构效关系及EGFR/抑制剂复合物晶体结构,选择喹唑啉为母核进行EGFR酪氨酸激酶抑制剂的设计与合成,共合成了87个目标化合物,并测定和分析了这些化合物的生物活性。首先,设计、合成了一系列喹唑啉并二氧六元环的衍生物。大部分的目标化合物表现了中等到显著的EGFRwt及EGFRT790M/L858R激酶抑制活性,其中21个化合物对EGFRwt激酶抑制活性小于50 n M,11个化合物对EGFRT790M/L858R突变激酶抑制活性小于100 n M。化合物N-(3-氯-4-氟苯基)-5-乙氧基-2,3-二氢-[1,4]二VA烷[2,3-f]喹唑啉-10-胺(29b1)具有最显著的EGFRwt(IC50=2.0 n M)及EGFRT790M/L858R(IC50=6.9 n M)激酶抑制活性。对激酶有显著抑制活性的化合物对肿瘤细胞H358及A549的增殖抑制能力也较强。另外,与对照药相比,大部分化合物对T293细胞毒性较低。基于上述研究成果,为探讨喹唑啉并六元氧杂环母核中六元氧杂环上取代基对生物活性的影响,设计并合成了一系列2,3-二氢-[1,4]二VA英[2,3-f]喹唑啉-10-胺衍生物,并评价这些化合物的EGFR激酶抑制活性。实验结果表明,所合成的22个目标化合物都有较好的抑制活性(10.29 n M≤IC50≤652.3 n M),其中化合物47b、47c、48b及48c对EGFRwt的抑制活性与对照药Gefitinib和Erlotinib相近,对激酶有显著抑制活性的化合物对NCI-H157肿瘤细胞的增殖也表现较强的抑制作用。与对照药相比,大部分化合物对T293细胞毒性较低。为进一步探讨母核结构与生物活性的关系,我们设计并合成了一系列吗啉酮并喹唑啉类衍生物,这些化合物大部分对EGFRwt激酶表现了较强的抑制活性。21个目标化合物中,19个的IC50值在53 n M到830 n M之间,其中4-(3-氯-4-氟苯基氨基)-6-(3-吗啉丙基)-6H-[1,4]恶嗪[3,2-g]喹唑啉-7(8H)-酮(60a8)显示出良好的的抑制效果,其IC50值为53.1 n M。对60a7与60a8进一步的生物活性研究表明,两个化合物对L858R/T790M突变的EGFR有较好的抑制作用。与对照药Gefitinib与Erlotinib相比,两个化合物对H358及A549细胞显示较强的增殖抑制作用。选取81个目标化合物进行三维定量构效关系研究,对29a2进行分子动力学模拟,结果合理解释化合物的构效关系,为进一步结构优化,发现新型EGFR酪氨酸激酶抑制剂提供了基础。
[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，

本文编号：1799134