Département de chimie moléculaire

Little is known about the biol. and structural features that govern the isoform selectivity for class I histone deacetylases (HDACs) over HDAC6. In addn. to that for known inhibitors, like benzamides, psammaplin A, and cyclodepsipeptide-derived thiols, selectivity was also obsd. for naturally occurring cyclopeptide HDAC inhibitors with an aliph. 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 enzymic assays. The best cyclopeptide-free analogs preserved efficacy against Plasmodium falciparum and cancer cell lines. Mol. 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. [on SciFinder(R)]