title: Design, Synthesis, Activity and Docking Study of Sorafenib Analogs Bearing Sulfonylurea Unit.
abstract: Two series of novel sorafenib analogs containing a sulfonylurea unit were synthesized and their chemical structures were confirmed by ¹H-NMR, ¹³C-NMR, MS spectrum and elemental analysis. The synthesized compounds were evaluated for the cytotoxicity against A549, Hela, MCF-7, and PC-3 cancer cell lines. Some of the compounds showed moderate cytotoxic activity, especially compounds 1-(2,4-difluorophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6c) and 1-(4-bromophenylsulfonyl)-3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (6f) with the IC50 values against four cancer cell lines ranging from 16.54±1.22 to 63.92±1.81 μM, respectively. Inhibitory rates against vascular endothelial growth factor receptor-2 (VEGFR2/KDR) kinase at 10 μM of target compounds were further carried out in this paper in order to investigate the target of these compounds. Structure-activity relationships (SARs) and docking studies indicated that the sulfonylurea unit was important to these kinds of compounds. None of the substitutions in the phenoxy group and small halogen atoms such as 2,4-difluoro substitution of the aryl group contributed to the activity. The results suggested that sulfonylurea sorafenib analogs are worthy of further study.
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. wuchunjiang999@126.com.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. wangmin6029@126.com.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. tangqidongcn@126.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Jiangxi Province Institute of Materia Medica, Nanchang 330000, China. 6350173@163.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. chenle182@163.com.
authors.forename: Le
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. Zhengpw@126.com.
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China. zhuwf@jxstnu.edu.cn.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D013453:Sulfonylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGFR2/KDR kinase inhibitors; anticancer activity; sorafenib; sulfonylurea