Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation

Abstract

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit <b>6a</b>. We identified compound <b>6j</b> as the most potent and selective <i>h</i>HDAC6 inhibitor of the series. Biological investigation of compounds <b>6b</b>, <b>6h</b>, and <b>6j</b> demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. <b>6j</b> induced HDAC6-dependent pSTAT3 inhibition.