title: Synthesis, Biological Evaluation and Docking Studies of Sorafenib Derivatives N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4(5)-phenylpicolinamides.
abstract: BACKGROUND
  Sorafenib is an important VEGFR2/KDR inhibitor which is widely used for the treatment of cancer.
  
  
  OBJECTIVE
  In this paper, two series of sorafenib analogues N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-4- phenylpicolinamides(13a-k) and N-(3-fluoro-4-(pyridin-4-yloxy)phenyl)-5-phenylpicolinamides (14a-k) were designed and synthesized.
  
  
  METHODS
  Their structures were confirmed by various analytical methods, such as 1 H and 13 C NMR, m.p., MS, HRMS. All of them were evaluated for IC50 values against three cancer cell lines (A549, PC-3 and MCF-7).
  
  
  RESULTS
  Eleven of the synthesized compounds showed moderate to excellent cytotoxicity activity against different cancer cells, whose potency from single-digit µM to nanomolar range. And five of them were equal to more potent than sorafenib against one or more cell lines. The most promising compound 14c showed excellent antitumor activities against PC-3 and MCF-7 cell lines with IC50 values of 2.62±1.07 µM and 1.14±0.92 µM, which were 1.15 to 2.75-fold more active than sorafenib (3.03±1.01 µM, 3.14±1.65 µM), respectively.
  
  
  CONCLUSIONS
  Structure-activity relationships (SARs) and docking studies indicated that the replacement of diarylurea of sorafenib with phenylpicolinamide moiety benefited to the activity. The position of aryl group and the substituents of aryl group had a great influence on antitumor activity and selectivity. The aryl groups with the substitute of alkyl groups (-CH3), halogen atoms (-F,Cl) were favorable to the cytotoxicity. However, this series of compounds showed moderate activity against VEGFR2/KDR kinase. Mechanism of target compounds was not quite clear and further study will be carried out to identify the possible target.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, P. R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Pengwu
authors.initials: P
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, P. R. China.
authors.forename: Wufu
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000737:chemistry*; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D010848:Picolinic Acids; D009536:Niacinamide; D000077157:Sorafenib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C003142:picolinamide
keywords: Picolinamides; VEGFR2/KDR; antitumor; docking; sorafenib