title: Synthesis of p-O-Alkyl Salicylanilide Derivatives as Novel EGFR Inhibitors.
abstract: Preclinical Research Epidermal growth factor receptor (EGFR), a validated target for anticancer drugs, plays a critical role in tumorigenesis and tumor development. A series of p-O-alkyl salicylanilide derivatives were designed and synthesized as novel EGFR inhibitors using a salicylic acid scaffold. A simulated six-membered ring strategy formed through intramolecular hydrogen bonds was employed to mimic the planar quinazoline of the EGFR antagonist, gefitinib. The derived compounds with hydroxyl at the ortho position were more potent than ones with methoxyl group. In particular, compounds 5d and 5b displayed significant EGFR inhibitory (IC50 values = 0.30 and 0.45 μM, respectively) activity as well as potent antiproliferative activity in A431 and HCT-116 tumor cells. These salicylanilides could be considered as promising lead compounds for developing novel EGFR inhibitors.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Biochemistry, Medical College, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Zidong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Jibo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Experimental Animal Center, Medical College, Qingdao University, Qingdao, Shandong, 266021, China.
authors.forename: Guiming
authors.initials: G
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D045325:HCT116 Cells; D006801:Humans; D006860:Hydrogen Bonding; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012458:Salicylanilides; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: epidermal growth factor receptor inhibitors; receptor tyrosine kinase; salicylanilide; salicylic acid