title: Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines.
abstract: A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib. Moreover, compound 7j is not sensitive to normal cells PBMC, indicating low cell cytotoxicity. In addition, flow cytometry analysis indicated that 7j significantly induced the apoptosis of Ramos cells, and arrested the cell cycle at the G0/G1 phase. These explorations provided new clues to discover pyrimidine scaffold as more effective BTK inhibitors.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Menghua
authors.initials: M
authors.lastname: Qu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaodong.ma@139.com.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian 116044, PR China. Electronic address: xiaohong_shu@dmu.edu.cn.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Shu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: BTK; Inhibitor; Leukemia; Pyrimidine; Synthesis