Novel histone deacetylase 6 inhibitors using benzimidazole as caps for cancer treatment

Abstract

Histone deacetylases (HDACs) have proven to be promising targets for the development of anticancer drugs. In this work, we report the design and synthesis of a series of 19 novel hydroxamic acid-based histone deacetylase inhibitors conjugated to benzimidazole and benzoxazole core structures. Five compounds showed anti-proliferative activity with an IC₅₀ value of 2.9–70.9 μM. Compound 7 displayed the highest efficacy against MCF-7 cells and exhibited antiproliferative effects against a panel of cancer cell lines. Compound 7 was the most potent selective inhibitor of HDAC6 and had an IC₅₀ value 8- to >111.1-fold those of HDAC3, HDAC4, HDAC8, and HDAC11, and was a superior HDAC6 inhibitor to belinostat. Its interaction with and inhibitory activity on HDAC enzymes were then explored in a molecular docking study. The obtained data revealed the highest binding affinity (−8.46 kcal mol⁻¹) of compound 7 toward HDAC6, as it formed interactions with the key residues Cys584 and Asp612 within the active site. Furthermore, the HDAC inhibitory activity of compound 7 was demonstrated from the dose-dependent increase in the tubulin acetylation level. Together, our results indicated that compound 7 with a cap of benzimidazole and four carbon-chain-containing thioether linker is a potent anticancer agent for selective HDAC6 inhibition and deserves further investigation.