Design, synthesis, and in vitro antitumor activity of 6-aryloxyl substituted quinazoline derivatives

Authors: MEIXIA FAN, LEI YAO

Abstract: 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 (EGFR^T790M/L858R), and A549 (EGFR^WT) 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.

Keywords: Quinazolines, antitumor, epidermal growth factor receptor, synthesis

Full Text: PDF