Design, synthesis and preliminary activity assay of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as novel Histone deacetylases (HDACs) inhibitors

Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC50 = 0.58 ± 0.10 μM), 7d (IC50 = 1.00 ± 0.16 μM), 8l (IC50 = 1.06 ± 0.14 μM), 7i (IC50 = 1.17 ± 0.19 μM) and 7a (IC50 = 1.29 ± 0.15 μM) possessed better HDACs inhibitory activity than Vorinostat (IC50 = 1.48 ± 0.20 μM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure–activity relationships are also briefly discussed.

The compounds 13a (IC50 = 0.58 ± 0.10 μM) and 7d (IC50 = 1.00 ± 0.16 μM) were docked into the active site of HDAC8 (PDB entry: 1T64) using SYBYL 7.3. Zinc ion is indicated. Y100 stands for the tyrosine 100 residue. The yellow arc indicates the pocket X of the protein. 13a is depicted in purple and 7d in white (atom type: polar H, sky-blue; N, dark blue; O, red).Figure optionsDownload as PowerPoint slide