Novel HDAC6 selective inhibitors with 4-aminopiperidine-1- carboxamide as the core structure enhanced growth inhibitory activity of bortezomib in MCF-7 cells.

In epigenetics, histone deacetylases (HDACs) are well validated targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of twenty two novel (E)-N-hydroxycinnamamide-based HDAC inhibitors with 4-aminopiperidine1-carboxamide as the core structure. Most newly synthesized compounds displayed high inhibition rates toward HDAC at the concentration of 1 μM. Among them, the inhibition rates of compounds LYP-2, LYP-3, LYP-6, and LYP-15 were more than 75%. Furthermore, compounds LYP-2, LYP-3, and LYP-6 potently inhibited the activity of HDAC6 with selectivity over HDAC1. We chose LYP-2 and LYP-6 to test its antiproliferative effect on breast cancer cells MCF-7. Either LYP-2 or LYP-6 alone moderately suppressed the cell growth, but could synergistically enhance the inhibitory effect of bortezomib. These results suggested that combined HDAC6 inhibitor and bortezomib regimen might be an option for breast cancer treatment.