title: Novel Quinazoline Derivatives Bearing Various 4-Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines.
abstract: A class of novel quinazoline derivatives bearing various C-4 aniline moieties was synthesized and biologically evaluated as potent epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Most of these inhibitors are comparable to gefitinib in inhibiting these cancer cell lines, and several of them even displayed superior inhibitory activity. In particular, analogue 5b with an IC50 of 0.10 μm against the EGFR wild-type A431 cells and 5c with an IC50 of 0.001 μm against the gefitinib-sensitive HCC827 cells (EGFR del E746-A750) was identified as highly active EGFR inhibitors. It was also significant that the discovered analogue 2f, not only has high potency against the gefitinib-sensitive cells (IC50 = 0.031 μm), but also possesses remarkably improved activity against the gefitinib-resistant cells. In addition, the enzymatic assays and the Western blot analysis for evaluating the effects of the typical inhibitors indicated that these molecules strongly interfere with the EGFR target.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Changyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Xingqi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Shu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, V5Z 4E8, Canada.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; C023650:aniline
keywords: EGFR; NSCLC; T790M; inhibitor; quinazoline