6-取代喹唑啉衍生物的设计、合成及其体外抗肿瘤活性
Design, synthesis, and in vitro antitumor activity of 6-aryloxyl substituted quinazoline derivatives.
发表日期：2022
作者：
Meixia Fan, Lei Yao
来源：
PHARMACOLOGY & THERAPEUTICS
摘要：
喹唑啉衍生物是一类重要的抗肿瘤药物，被称为小分子抑制剂，其中包括表皮生长因子受体（EGFR）抑制剂。根据泊津呋替尼的结构，设计并合成了一系列6-芳氧基取代的喹唑啉衍生物。通过人胃癌细胞系N87（HER2）、非小细胞肺癌细胞系H1975（EGFR T790M/L858R）和A549（EGFR WT）细胞系使用3-(4,5-二甲基噻唑-2-基) 2,5-二苯基四唑溴化物（MTT）法评估了这些化合物的体外抗肿瘤活性。其中最有潜力的化合物4m在N87和H1975细胞系中表现出了明显的抗肿瘤活性，IC50值分别为6.3 nM和7.5 nM。与此同时，对于A549癌细胞，其抗肿瘤活性较弱，IC50值为29.9 μM。分子对接结果表明，化合物4m对野生型和突变型EGFR有不同的结合方式。© TÜBİTAK.
Quinazoline derivatives are a class of important antitumor drugs known as small molecule inhibitors that include epidermal growth factor receptor (EGFR) inhibitors. Based on the structure of poziotinib, a series of 6-aryloxyl substituted quinazoline derivatives were designed and synthesized. The in vitro antitumor activities of the compounds were evaluated by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method using the human gastric cancer N87 (HER2), nonsmall-cell lung cancer H1975 (EGFRT790M/L858R), and A549 (EGFRWT) cell lines. The most promising compound 4m exhibited potent antitumoral activities with IC50 values of 6.3 nM and 7.5 nM for N87 and H1975 cell lines, respectively. Meanwhile, it was less potent against A549 cancer cells with an IC50 value of 29.9 μM. The molecular docking results suggested that compound 4m has different binding modes to the wild-type and mutated EGFR.© TÜBİTAK.