Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors

The design, synthesis and biological evaluation of a series of isoquinoline-based hydroxamic acid compounds as novel HDACs inhibitors were reported herein. A detailed SAR study showed most of the compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10c against HDAC1, 3, 6 were 4.17 +/- 0.11 nM, 4.00 +/- 0.10 nM, 3.77 +/- 0.07 nM, respectively. Most of the compounds showed great anti-proliferative activities against RPMI 8226, HCT 116 and Hep G2 cells. The IC50 values of compounds 10a-h against RPMI 8226 cancer cell proliferation were all below 1 mu M. HCT 116 cell was sensitive to the compounds 10a, 10f-g and 18a with the IC50 values <0.3 mu M. The active compounds 10a-d did not show inhibitory activity against hERG channel. All these evidence indicated these compounds had great potential as HDACs inhibitors for the further development. (C) 2015 Elsevier Ltd. All rights reserved.