[摘要]：Inhibition of histone deacetylase inhibitors (HDACi) hold great promise in cancer therapy because of their demonstrated ability to arrest proliferation of nearly all transformed cell types. Of the several structurally distinct small mol. HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biol. activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compds. have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addn. to retaining the pharmacol. disadvantaged peptidyl backbone, they offer only limited opportunity for side chain modifications. Here, we report the discovery of a new class of macrocyclic HDACi based on the macrolide antibiotics skeletons. SAR studies revealed that these compds. displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC50 in the low nanomolar range. In addn., these non-peptide macrocyclic HDACi are more selective against HDACs 1 and 2 relative to HDAC 8, another class I HDAC isoform, and hence have subclass HDAC isoform selectivity.
