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

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

Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells

Jumonji AT-rich interactive domain 1A (JARID1A), one of the jumonji C domain-containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARID1A inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in-house library and the structural optimization based on docking study of the hit-compound to a homology model of JARID1A. As a result, we identified compound <b>6j</b>, which selectively inhibits JARID1A over three other JHDM family members. Compound <b>7j</b>, a prodrug form of compound <b>6j</b>, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound <b>7j</b> synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARID1A inhibitors have potential as anticancer agents

Scheme for the synthesis of T247 and T326.

<p>Reagents and conditions: (a) CuSO₄, sodium ascorbate, EtOH, H₂O, room temp, 65% for <b>T247</b>; 97% for <b>T326</b>.</p

HDAC-Inhibitory Activity of vorinostat (3), compound 1, T247, and T326 ^a.

a<p>Values are means of at least three experiments.</p

Binding mode of T247.

<p>(A) View of the conformation of <b>T247</b> (tube) docked in the HDAC3 catalytic core. Compound <b>T247</b> was docked into a model based on the crystal structure of HDAC3 (PDB code 4A69) using the Molegro Virtual Docker software package. Residues around <b>T247</b> are displayed as wires. (B) The same view as A. The narrow and long tunnel of the active site is displayed as a green mesh. (C) Schematic diagram of <b>T247</b>-binding to the catalytic site.</p

HDAC3 inhibition in the presence of vorinostat (3), compound 1, and 11 o-aminoanilides at 1 µM and 3 µM.^a

a<p>Values are means of two experiments.</p

Design of triazole-containing HDAC inhibitor candidates.

<p>Design of triazole-containing HDAC inhibitor candidates.</p

Total HDACs activity in the presence of 48 hydroxamates (1 µM).

<p>Total HDACs activity in the presence of 48 hydroxamates (1 µM).</p

Scheme for the synthesis of Ak1–Ak3.

<p>Reagents and conditions: (a) EDCI, HOBt, DMF, room temp, 36–62%.</p

Previously reported HDAC3-selective inhibitors 1 and 2.

<p>Previously reported HDAC3-selective inhibitors 1 and 2.</p