Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors

Histone
deacetylase 6 (HDAC6) catalyzes the removal of an acetyl
group from lysine residues of several non-histone proteins. Here we
report the preparation of thiazole-, oxazole-, and oxadiazole-containing
biarylhydroxamic acids by a short synthetic procedure. We identified
them as selective HDAC6 inhibitors by investigating the inhibition
of recombinant HDAC enzymes and the protein acetylation in cells by
Western blotting (tubulin vs histone acetylation). The most active
compounds exhibited nanomolar potency and high selectivity for HDAC6.
For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of >200 against
HDAC1
and HDAC8. This is the first report showing that the nature of a heterocycle
directly connected to a zinc binding group (ZBG) can be used to modulate
subtype selectivity and potency for HDAC6 inhibitors to such an extent.
We rationalize the high potency and selectivity of the oxazoles by
molecular modeling and docking.