title: Design, synthesis and activity of novel sorafenib analogues bearing chalcone unit.
abstract: Two series of sorafenib derivatives (N-methylpicolinamide-4-oxy) chalcones (5a-o, 7a-e) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC50values of 0.56±0.83μM, 3.88±1.03μM and 3.15±0.81μM, which were 1.03-6.14-fold more active than sorafenib (3.44±1.50μM, 3.18±1.43μM, 3.24±0.45μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC50value was 0.72μM. Structure-activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity.
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Min
authors: M
authors: Wang
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: shanxu9891@126.com.
authors: Shan
authors: S
authors: Xu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Chunjiang
authors: C
authors: Wu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Xiaobo
authors: X
authors: Liu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Hong
authors: H
authors: Tao
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Yanli
authors: Y
authors: Huang
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Yongchan
authors: Y
authors: Liu
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China.
authors: Pengwu
authors: P
authors: Zheng
authors: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China. Electronic address: zhuwf@jxstnu.edu.cn.
authors: Wufu
authors: W
authors: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D002599:Chalcone; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: (N-Methylpicolinamide-4-oxy) chalcones; Anticancer activity; Sorafenib derivatives; VEGFR-2/KDR kinase inhibitors