title: Discovery of novel Bcr-Abl inhibitors with diacylated piperazine as the flexible linker.
abstract: Forty-two compounds (series 8, 9 and 10) incorporated with diacylated piperazine have been synthesized and evaluated as novel Bcr-Abl inhibitors based on 'six-atom linker'. Five of them, 8d, 8h, 8l, 10m and 10p, displayed potent Bcr-Abl inhibitory activity comparable with Imatinib. Moreover, compounds 8e, 10q, 10s, and 10u were potent Bcr-Abl inhibitors with IC50 values at the sub-micromolecular level. Most compounds exhibited moderate to high antiproliferative activity against K562 cells. In particular, compound 9e was the most promising Bcr-Abl inhibitor. Docking studies revealed that the binding modes of these compounds were similar with Imatinib. These compounds could be considered as promising lead compounds for further optimization.
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, P.R. China. zhj8623@mail.xjtu.edu.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pan
authors.forename: Jinyun
authors.initials: J
authors.lastname: Dong
authors.forename: Yaling
authors.initials: Y
authors.lastname: Shi
authors.forename: Ruili
authors.initials: R
authors.lastname: Shao
authors.forename: Fen
authors.initials: F
authors.lastname: Wei
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000215:Acylation; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D000077489:Piperazine; D016044:Fusion Proteins, bcr-abl