Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6

Little
is known about the biological and structural features that
govern the isoform selectivity for class I histone deacetylases (HDACs)
over HDAC6. In addition to that for known inhibitors, like benzamides,
psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was
also observed for naturally occurring cyclopeptide HDAC inhibitors
with an aliphatic flexible linker and ketonelike zinc-binding group
(ZBG). The present study reports that this isoform selectivity is
mainly due to the linker and ZBG, as replacement of the cyclopeptide
cap region by a simple aniline retained class I HDAC isoform selectivity
toward HDAC6 in enzymatic assays. The best cyclopeptide-free analogues
preserved efficacy against Plasmodium falciparum and cancer cell lines. Molecular modeling provided hypotheses to
explain this selectivity and suggests different behaviors of the flexible
linker on HDAC1 and HDAC6 pockets, which may influence, on the basis
of the strength of the ZBG, its coordination with the zinc ion.