Abstract
Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.
Highlights
Cancer is set to become a major cause of morbidity and mortality, and is a major public health problem worldwide[1,2]
As the pathogenesis of cancer continues to clarify, many biological targets including epidermal growth factor receptor (EGFR) have been identified playing a key role in the development of a number of the most lethal cancers, and the activity of EGFR-specific tyrosine kinase inhibitors (TKIs) against such cancers ushered in an era of genotype-directed targeted therapy that fundamentally changed the overall approach to lung cancer[5]
Gefitinib and erlotinib have been referred as the first generation of EGFR-TKIs4,8, and lapatinib was a dual EGFR and human epidermal growth factor receptor-2 (HER-2) inhibitors[9]
Summary
Cancer is set to become a major cause of morbidity and mortality, and is a major public health problem worldwide[1,2]. Gefitinib and erlotinib have been referred as the first generation of EGFR-TKIs4,8, and lapatinib was a dual EGFR and human epidermal growth factor receptor-2 (HER-2) inhibitors[9]. They have been all approved for cancer treatment by the US Food and Drug Administration (FDA). These drugs have some limits in clinical usage, such as drug resistance of gefitinib[10,11], hepatotoxicity of lapatinib[12,13], and erlotinib has similar toxic-effect profiles with gefitinib[14]. Ever since FDA approval of “Gefitinib” in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor “Osimertinib” in 2015, finding more efficient EGFR-TKIs are still going on due to the continuous emergence of resistance to the current inhibitors[15]
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