title: Late-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 Analogues.
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.
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University , Chikusa, Nagoya 464-8602, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sekizawa
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University , Chikusa, Nagoya 464-8602, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Amaike
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 13 Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto 603-8334, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: 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.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Itami
authors.affiliation: Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University , Chikusa, Nagoya 464-8602, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamaguchi
keywords: C−H coupling; HDAC6; Histone deacetylase; inhibitor