N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: design, synthesis, SAR studies, and in vivo antitumor activity

  • Bioorg Med Chem Lett. 2009 Mar 1;19(5):1403-8. doi: 10.1016/j.bmcl.2009.01.041.
Haishan Wang  1 ,  Niefang Yu ,  Hongyan Song ,  Dizhong Chen ,  Yong Zou ,  Weiping Deng ,  Pek Ling Lye ,  Joyce Chang ,  Melvin Ng ,  Eric T Sun ,  Kanda Sangthongpitag ,  Xukun Wang ,  Xiaofeng Wu ,  Hwee Hoon Khng ,  Lijuan Fang ,  Siok Kun Goh ,  Wai Chung Ong ,  Zahid Bonday ,  Walter Stünkel ,  Anders Poulsen ,  Michael Entzeroth
Affiliations
  • 1. S *BIO Pte Ltd, 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore.
PMID: 19181524 DOI: 10.1016/j.bmcl.2009.01.041
Abstract

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.