Synthesis and SAR of N-hydroxy-1,2-disubstituted-1H-benzoimidazol-5-yl-acrylamides as a novel class of histone deacetylase inhibitors

MEDI 146

Haishan Wang, haishan_wang@sbio.com1, Niefang Yu1, Hongyan Song1, Dizhong Chen1, Weiping Deng1, Pek Ling Lye1, Yong Zou1, Melvin Ng1, Joyce Chang1, Eric T Sun1, Kanda Sangthongpitag2, Xukun Wang2, Xiaofeng Wu2, Hwee Hoon Khng2, Siok Kun Goh2, Pauline Yeo3, Xin Liu3, Evelyn Goh3, Lee Sun New3, Kantharaj Ethirajulu3, and Michael Entzeroth2. (1) Medicinal Chemistry, S*BIO Pte Ltd, 1 Science Park Road #05-09 The Capricorn, Singapore Science Park II, Singapore, 117528, Singapore, (2) Drug Discovery Biology, S*BIO Pte Ltd, (3) Pharmacokinetics and Drug Metabolism, S*BIO Pte Ltd
Histone deacetylase (HDAC) inhibitors have emerged as a new class of therapeutic agents for cancers. We have designed and synthesized a series of N-hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel HDAC inhibitors. SAR of substituents on the benzimidazole ring were explored and established. A good correlation between HDAC1 inhibition data (IC50) and anti-proliferative data (GI50) was established. Within this series, selected compounds were evaluated in animal models for anti-tumor activity. A representative compound SB639 (1) produced significant tumor growth inhibition and tumor growth delay in HCT116 bearing nude mice xenograft model. SB639 also increased the level of acetylation of histone H3 in tumor tissues for up to 24 h. In this presentation, the synthesis, SAR and biological profiles of this series of inhibitors will be discussed.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006