title: Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors.
abstract: Two series of afatinib derivatives bearing cinnamamide moiety (10a-n and 11a-h) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, PC-3, MCF-7 and Hela). Two selected compounds (10e, 10k) were further evaluated for the inhibitory activity against EGFR and VEGFR2/KDR kinases. Seven of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Three of them are equal to more active than positive control afatinib against one or more cell lines. The most promising compound 10k showed the best activity against A549, PC-3, MCF-7 and Hela cancer cell lines and EGFR kinase, with the IC50 values of 0.07 ± 0.02 μM, 7.67 ± 0.97 μM, 4.65 ± 0.90 μM and 4.83 ± 1.28 μM, which were equal to more active than afatinib (0.05 ± 0.01 μM, 4.1 ± 2.47 μM, 5.83 ± 1.89 μM and 6.81 ± 1.77 μM), respectively. Activity of compounds 10e (IC50 9.1 nM) and 10k (IC50 3.6 nM) against EGFR kinase were equal to the reference compound afatinib (IC50 1.6 nM). Structure-activity relationships (SARs) and docking studies indicated that replacement of the aqueous solubility 4-(dimethylamino)but-2-enamide group by cinnamamide moiety didn't decrease the antitumor activity. The results suggested that methoxy substitution had a significant impact on the activity and methoxy substituted on C-4 or C-2,3,4 position was benefit for the activity.
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Yuanbiao
authors.initials: Y
authors.lastname: Tu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: OuYang
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: shanxu9891@126.com.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.affiliation: School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhuwf@jxstnu.edu.cn.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000077716:Afatinib; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002934:Cinnamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; C411088:cinnamamide
keywords: Afatinib; Antitumor activity; Cinnamamide; Docking; EGFR inhibitors; Synthesis