Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity.
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.
Bressi
Jerome C
JC
Takeda San Diego, San Diego, CA 92121, USA.
de Jong
Ron
R
Wu
Yiqin
Y
Jennings
Andy J
AJ
Brown
Jason W
JW
O'Connell
Shawn
S
Tari
Leslie W
LW
Skene
Robert J
RJ
Vu
Phong
P
Navre
Marc
M
Cao
Xiaodong
X
Gangloff
Anthony R
AR
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
D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; C029899:imidazole; D006655:Histone Deacetylases