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Chem Biol Drug Des. 2017 Jan;89(1):38-46. doi: 10.1111/cbdd.12819. Epub 2016 Oct 26.

Design, synthesis, and preliminary bioactivity evaluation of N1 -hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors.

Wang X1, Li X1, Li J1, Hou J1, Qu Y1, Yu C1, He F1, Xu W1, Wu J1.

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Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong, China.


Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50  = 0.074 μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50  = 0.131 μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.


HDACIs; antiproliferative activity; molecular docking; selectivity

[Indexed for MEDLINE]

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