title: Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity.
abstract: A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC(50)s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21(waf). Compound 5x displays efficacy in human tumor xenograft models.
authors.affiliation: Takeda San Diego, San Diego, CA 92121, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Bressi
authors.forename: Ron
authors.initials: R
authors.lastname: de Jong
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Wu
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Jennings
authors.forename: Jason W
authors.initials: JW
authors.lastname: Brown
authors.forename: Shawn
authors.initials: S
authors.lastname: O'Connell
authors.forename: Leslie W
authors.initials: LW
authors.lastname: Tari
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Skene
authors.forename: Phong
authors.initials: P
authors.lastname: Vu
authors.forename: Marc
authors.initials: M
authors.lastname: Navre
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cao
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Gangloff
mesh_terms: D000107:Acetylation; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; C029899:imidazole; D006655:Histone Deacetylases