Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors

To uncover novel histone deacetylase 6 (HDAC6)-selective inhibitors and to elucidate the structural requirements for their inhibitory activity, we designed and prepared a series of thiolate analogues based on the structure of an HDAC6-selective substrate and evaluated their properties by Western blotting and enzyme assays. Several thiolate analogues were found to be potent and selective HDAC6 inhibitors. Study of the structure-selectivity relationship revealed that the presence of a bulky alkyl group and tert-butylcarbamate group in these compounds is important for HDAC6-selective inhibition. Compounds 16b and 20b, the most selective and active compounds in this series, exerted a synergistic inhibition of Cancer cell growth in combination with paclitaxel. They also blocked the growth of Estrogen receptor alpha-positive breast Cancer MCF-7 cells that had been treated with estrogen. These findings suggested that HDAC6-selective inhibitors have potential as Anticancer agents.