Design,synthesis, and biological evaluation of novel histone deacetylase 6 selective inhibitors

Histone deacetylase 6 (HDAC6) is distinguished from other HDACs by its ability to deacetylate α-tubulin and HSP90, and was reported to be related to a variety of human diseases, such as cancers, neurodegenerative diseases, and immunological disorders. The discovery of novel HDAC6 selective inhibitors is important directions of this research field. In this paper, on the basis of a Bcl-2/HDAC6 dual target inhibitor 7g reported by us previously, a novel type of HDAC6 inhibitors was obtained by removing the binding capability to Bcl-2 protein and the subsequent systematical optimization. Among them, compounds Ⅵ-9, Ⅵ-10 and Ⅵ-11 (IC₅₀ = 3.2 ～ 3.9 nM, SI = 20.6 ～ 38.7) showed the best inhibitory activities against and excellent selectivity to HDAC6. These compounds displayed growth inhibitory selectivity to human multiple myeloma cell line over normal cell line, which indicated potential lower toxicity to normal cells and tissues.