Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation

Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform
whose
expression and functional alterations have been correlated with a
variety of pathologies such as autoimmune disorders, neurodegenerative
diseases, and cancer. It is primarily a cytoplasmic protein, and its
deacetylase activity is focused mainly on nonhistone substrates such
as tubulin, heat shock protein (HSP)­90, Foxp3, and cortactin, to name
a few. Selective inhibition of HDAC6 does not show cytotoxic effects
in healthy cells, normally associated with the inhibition of Class
I HDAC isoforms. Here, we describe the design and synthesis of a new
class of potent and selective HDAC6 inhibitors that bear a pentaheterocyclic
central core. These compounds show a remarkably low toxicity both
in vitro and in vivo and are able to increase the function of regulatory
T cells (Tregs) at well-tolerated concentrations, suggesting a potential
clinical use for the treatment of degenerative, autoimmune diseases
and for organ transplantation.