Oxa analogues of nexturastat A demonstrate improved HDAC6 selectivity and superior anti-leukaemia activity.

The acetylome is important to maintain the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases and degeneration might promote the manifestation of cancer. Particularly, the pharmacological intervention of the acetylome with pan-histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk-benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6 selective inhibitors. During our lead structure identification, we demonstrated that a hydroxylamine subunit proves to be beneficial for HDAC6 selectivity and established the synthesis of N -alkoxyurea based hydroxamic acids 4. Here we report highly potent N -alkoxyurea based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastat A.