title: Design and synthesis of a tetrahydroisoquinoline-based hydroxamate derivative (ZYJ-34v), an oral active histone deacetylase inhibitor with potent antitumor activity.
abstract: In our previous study, we developed a novel series of tetrahydroisoquinoline-based hydroxamic acid derivatives as histone deacetylase inhibitors (Bioorg Med Chem, 2010, 18, 1761-1772; J Med Chem, 2011, 54, 2823-2838), among which, compound ZYJ-34c (1) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency (J Med Chem, 2011, 54, 5532-5539.). Herein, further modification in 1 afforded another oral active analog ZYJ-34v (2) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against histone deacetylase 1, 2, 3, and 6, which was confirmed by Western blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved histone deacetylase inhibitor SAHA.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunxi
authors.initials: C
authors.lastname: Liu
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.forename: Xuejian
authors.initials: X
authors.lastname: Wang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Jia
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology
chemical_list: C561594:2-(2-(3,3-dimethylbutanamido)-3-methylpentanoyl)-7-(2-(hydroxyamino)-2-oxoethoxy)-N-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007546:Isoquinolines
keywords: antitumor; histone deacetylases; inhibitor; oral active; tetrahydroisoquinoline; valproic acid