title: Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents.
abstract: Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N-(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 μM) and antitumor activity with IC50 value of as low as 3.84 μM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer.
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xie
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China. Electronic address: tangpw@mail.buct.edu.cn.
authors.forename: Pingwah
authors.initials: P
authors.lastname: Tang
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Chen
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yun
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Wu
authors.affiliation: Medicinal Chemistry Research Division, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing 100029, China. Electronic address: yuanqp@mail.buct.edu.cn.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Yuan
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D062367:ortho-Aminobenzoates; D056464:Histone Deacetylase 2; C000219:anthranilamide
keywords: 2-Aminobenzamides; Antiproliferation; Histone deacetylase inhibitor; Hydroxamates; Molecular docking