title: Non-peptide macrocyclic histone deacetylase inhibitors.
abstract: 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 molecule HDACi reported, macrocyclic depsipeptides have the most complex recognition cap-group moieties and present an excellent opportunity for the modulation of the biological activities of HDACi. Unfortunately, the structure-activity relationship (SAR) studies for this class of compounds have been impaired largely because most macrocyclic HDACi known to date comprise complex peptide macrocycles. In addition to retaining the pharmacologically 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 compounds displayed both linker-length and macrolide-type dependent HDAC inhibition activities with IC(50) in the low nanomolar range. In addition, 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.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA. aoyelere@gatech.edu
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
authors.forename: Po C
authors.initials: PC
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Guerrant
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Mwakwari
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hood
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Fan
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D047028:Macrocyclic Compounds