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

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

Hiromi Sekizawa  1 , Kazuma Amaike  1 , Yukihiro Itoh  2 , Takayoshi Suzuki  3 , Kenichiro Itami  4 , Junichiro Yamaguchi  1
Affiliations

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

Hiromi Sekizawa et al. ACS Med Chem Lett. .

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.

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Figures

Figure 1
Figure 1
HDAC inhibitors: vorinostat, romidepsin, and NCH-31.
Figure 2
Figure 2
Synthesis of NCH-31 derivatives through classical and C–H functionalization routes.
Figure 3
Figure 3
Synthesis of NCH-31 analogues (IYS-1–15 and IYS-Me) by C–H coupling. Reaction conditions: (a) EDC·HCl (1.4 equiv), CH2Cl2, 23 °C, 6 h, 80%; (b) AcSK (4.0 equiv), EtOH, 23 °C, 16 h, 98%; (c) ArB(OH)2 (4.0 equiv), Pd(OAc)2 (10 mol %), phen (10 mol %), LiBF4 (1.5 euqiv), TEMPO (1.0 equiv), AcOH (1.0 equiv), DMAc, 100 °C, 10–29%; (d) K2CO3, MeOH, 23 °C; (e) MeI, NaH, DMF, 23 °C; (f) NH2NH2, CH3CN; then dithiothreitol, NEt3, 23 °C.
Figure 4
Figure 4
HDAC activity in the presence of IYS-1–15 and IYS-Me: blue bar for HDAC1 (enzyme activity % at 0.1 μM), purple bar for HDAC6 (enzyme activity % at 1 μM), and brown bar for HDAC9 (enzyme activity % at 0.1 μM).
Figure 5
Figure 5
(A) View of the conformation of IYS-15 (ball and stick model) docked in the HDAC1 catalytic core. (B) View of the conformation of NCH-31 (ball and stick model) docked in the HDAC1 catalytic core.
Figure 6
Figure 6
(A) View of the conformation of NCH-31 (ball and stick model) docked in the HDAC6 catalytic core. (B) View of the conformation of IYS-14 (ball and stick model) docked in the HDAC6 catalytic core. (C) Superimposition of IYS-14 (purple) and NCH-31 (green) in the active site of HDAC6.
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