The histone deacetylases (HDACs) are involved in the epigenetic regulation of gene transcription, among other roles, through the removal of acetyl groups from the lysine side chains of histone (and non-histone) proteins. As a result of this significant responsibility, the HDACs play key roles in a range of physiological processes, and as such, they have become important targets for multiple pathophysiologies, including cancer and neurodegenerative diseases. There are eighteen isoforms of HDACs, which are divided into four classes: class I (HDAC1-3, HDAC8), class IIa (HDAC4-5, HDAC7 and HDAC9) and IIb (HDAC6 and HDAC10), class III (the sirtuins) and class IV (HDAC11). The basic pharmacophore of HDAC inhibitors (HDACis) comprises a zinc-binding group (ZBG) that is coupled to a “cap” group through a linker; the cap group interacts with residues on the surface of the HDAC active site, whilst the ZBG binds the zinc ion in the active site pocket that is crucial to the deacetylase function. Currently, four HDACis have received US FDA approval. However, these inhibitors, which all possess hydroxamic acid as the ZBG, are associated with many side effects; this has been attributed to their pan-HDAC inhibitory activities. It is believed that HDAC isoform selectivity will yield more effective therapeutics with fewer side effects. The ortho-aminoanilide functionality is an alternative ZBG that is selective for class I HDACs, most particularly HDAC1-3, wherein the amino group and the carbonyl oxygen of the amide chelate the zinc ion. Further affinity and selectivity for HDAC1-3 appear to be attainable through building off the phenyl ring of this ZBG into the so-called “foot-pocket”. In the US, HDACs bearing the ortho-aminoanilide ZBG are yet to receive FDA approval, and this may be due, in part, to the toxicity associated with anilines from which this ZBG is constructed. Therefore, beginning with a previously reported class I selective HDACi based on an ortho-aminoanilide ZBG that also reaches into the foot-pocket, we are exploring a variety of non-aniline-based surrogate ZBGs that are equipped to retain both chelation of the zinc ion and foot-pocket recognition. The inhibitory activities and selectivities of our ortho-aminoanilide bioisosteres will be discussed.

Towards the bioisosteric replacement of the ortho-aminoanilide zinc-binding group in group I selective HDAC inhibitors

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