title: Synthesis and biological evaluation of novel aromatic-heterocyclic biphenyls as potent anti-leukemia agents.
abstract: As a continuation to our previous research, twenty-eight aromatic-heterocyclic biphenyls were designed and synthesized as novel Bcr-Abl inhibitors. The title compounds were investigated for their antiproliferative activities against wild K562 cells and Imatinib-resistant K562 cells (K562R). The results indicated that most of them exhibited potent Bcr-Abl inhibition and moderate antiproliferative potency against K562 cells. Furthermore, three compounds 3, 7 and 21 displayed moderate antiproliferative activities against K562R cells. Molecular docking indicated that 3 bound more tightly with Bcr-Abl(T315I) compared to Bcr-Abl(WT). The higher affinity was consistent with its relatively promising K562R cell growth inhibition. These aromatic-heterocyclic biphenyls could be considered as novel lead compound for optimized as Bcr-Abl(T315I) inhibitors. They provide a good starting point for the further development of novel anti-leukemia agents capable of dealing with clinical acquired resistance against Imatinib.
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Dong
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wei
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000473:pathology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D016044:Fusion Proteins, bcr-abl; D006571:Heterocyclic Compounds; C406060:abl-bcr fusion protein, human; C010574:biphenyl
keywords: Bcr–Abl inhibitors; Biphenyls; CML; Resistant