title: Discovery of a tetrahydroisoquinoline-based hydroxamic acid derivative (ZYJ-34c) as histone deacetylase inhibitor with potent oral antitumor activities.
abstract: Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, PR China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.forename: Jinhong
authors.initials: J
authors.lastname: Feng
authors.forename: Yuping
authors.initials: Y
authors.lastname: Jia
authors.forename: Xuejian
authors.initials: X
authors.lastname: Wang
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
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; D054697:Cytostatic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007546:Isoquinolines; D000077337:Vorinostat