N-Hydroxy-(4-oxime)-cinnamide: A versatile scaffold for the synthesis of novel histone deacetilase (HDAC) inhibitors

With the aim to discover novel HDAC inhibitors with high potency and good safety profiles, we have designed a small library based on a N-hydroxy-(4-oxime)-cinnamide scaffold. We describe the synthesis of these novel compounds and some preliminary in vitro cytotoxic activity on three tumor cell lines, NB4, H460 and HCT116, as well as their inhibitory activity against class I, II and IV HDAC. Several 4-oxime derivatives demonstrated a promising inhibitory activity on HDAC6 and HDAC8 coupled to a good selectivity profile.

Graphical abstractA small library of N-Hydroxy-(4-Oxime)-Cinnamide-based scaffold derivatives has been described. SAR has been established for R, oxyme moiety and X cinnamoyl-based HDAC inhibitors. Several 4-oxime derivatives demonstrated a promising inhibitory activity on HDAC6 and HDAC8 coupled to a good selectivity profile. Analogue 12 (ST2987) constitutes a promising lead compound for further optimization towards the identification of a clinical candidate.Figure optionsDownload full-size imageDownload as PowerPoint slide