Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin.
Seventy-two hundred potential inhibitors of the histone deacetylase (HDAC) enzyme family, based on a 1,3-dioxane diversity structure, were synthesized on polystyrene macrobeads. The compounds were arrayed for biological assays in a "one bead-one stock solution" format. Metal-chelating functional groups were used to direct the 1,3-dioxanes to HDAC enzymes, which are zinc hydrolases. Representative structures from this library were tested for inhibitory activity and the 1,3-dioxane structure was shown to be compatible with HDAC inhibition. [structure: see text]
Sternson
S M
SM
Howard Hughes Medical Institute (HHMI), Institute of Chemistry and Cell Biology (ICCB), Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Wong
J C
JC
Grozinger
C M
CM
Schreiber
S L
SL
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; C067070:trapoxin A; D006655:Histone Deacetylases