title: Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6.
abstract: A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having a potency of approximately 2 picomolar was identified. Some of the compounds were examined for their ability to block pancreatic cancer cell growth and found to be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes for use in exploring HDAC biology.
authors.affiliation: Department of Medicinal Chemistry & Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA. Kozikowa@uic.edu
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Subhasish
authors.initials: S
authors.lastname: Tapadar
authors.forename: Doris N
authors.initials: DN
authors.lastname: Luchini
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D015335:Molecular Probes; D009570:Nitriles; D010087:Oxides; D006655:Histone Deacetylases