<i>Ortho</i> -Hydroxyanilides: Slow-Acting, Selective Histone Deacetylase 1/2 Inhibitors Suitable for Photocaging Applications

Histone deacetylases (HDACs) regulate gene expression and are promising targets in oncology. Especially the class I isoforms HDAC1 and HDAC2 are overexpressed in cancer. However, while <i>ortho</i>-aminoanilides with a suitable (het)-aryl substitution are well-characterized HDAC1/HDAC2 inhibitors, the corresponding phenol analogs have not been sufficiently investigated so far. To this end, we compared the <i>ortho</i>-hydroxyanilide derivative <b>ST13</b> with the pan-HDAC inhibitor vorinostat and Cpd-60, an <i>ortho</i>-aminoanilide with high HDAC1/HDAC2 selectivity. <b>ST13</b> was further developed into a light-activatable prodrug (<b>ST17</b>) by masking its zinc-binding group with a photoremovable 4,5-dimethoxy-2-nitrobenzyl protecting group. Overall, we verified that <b>ST13</b> is a selective, slow- and tight-binding HDAC1/HDAC2 inhibitor with antiproliferative activity. Furthermore, we demonstrated that the light-activatable prodrug <b>ST17</b> readily releases <b>ST13</b> upon irradiation, thereby allowing to precisely control its antiproliferative properties. These findings validate <i>ortho</i>-hydroxyanilides as effective HDAC1/HDAC2-selective inhibitors and highlight photocaging as a promising strategy to achieve spatiotemporal control of epigenetic therapies in cancer.