N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: design, synthesis, SAR studies, and in vivo antitumor activity.
A series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides were designed and synthesized as novel HDAC inhibitors. General SAR has been established for the substituents at positions 1 and 2, as well as the importance of the ethylene group and its attachment to position 5. Optimized compounds are much more potent than SAHA in both enzymatic and cellular assays. A representative compound, 23 (SB639), has demonstrated antitumor activity in a colon cancer xenograft model.
Wang
Haishan
H
S *BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore.
Yu
Niefang
N
Song
Hongyan
H
Chen
Dizhong
D
Zou
Yong
Y
Deng
Weiping
W
Lye
Pek Ling
PL
Chang
Joyce
J
Ng
Melvin
M
Sun
Eric T
ET
Sangthongpitag
Kanda
K
Wang
Xukun
X
Wu
Xiaofeng
X
Khng
Hwee Hoon
HH
Fang
Lijuan
L
Goh
Siok Kun
SK
Ong
Wai Chung
WC
Bonday
Zahid
Z
Stünkel
Walter
W
Poulsen
Anders
A
Entzeroth
Michael
M
D000178:Acrylamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000178:Acrylamides; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases