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 alpha-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 similar to 3.9 nM, SI = 20.6 similar to 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. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of King Saud University.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study aimed to discover novel HDAC6 selective inhibitors, and a new class of compounds with excellent inhibitory activities and selectivity was obtained through structural optimization of the previously reported inhibitor 7g. These compounds showed inhibitory effects on HDAC6, a protein associated with diseases such as cancer, and may have lower toxicity to normal cells and tissues.