Late-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 Analogues

Hiromi Sekizawa; Kazuma Amaike; Yukihiro Itoh; Takayoshi Suzuki; Kenichiro Itami; Junichiro Yamaguchi

doi:10.1021/ml500024s

Late-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 Analogues

ACS Med Chem Lett. 2014 Mar 3;5(5):582-6. doi: 10.1021/ml500024s. eCollection 2014 May 8.

Authors

Hiromi Sekizawa¹, Kazuma Amaike¹, Yukihiro Itoh², Takayoshi Suzuki³, Kenichiro Itami⁴, Junichiro Yamaguchi¹

Affiliations

¹ Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University , Chikusa, Nagoya 464-8602, Japan.
² Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 603-8334, Japan.
³ Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 603-8334, Japan ; JST, PRESTO , 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
⁴ Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University , Chikusa, Nagoya 464-8602, Japan ; JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University , Chikusa, Nagoya 464-8602, Japan.

Abstract

We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules.

Keywords: C−H coupling; HDAC6; Histone deacetylase; inhibitor.