title: Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes.
abstract: The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
authors.forename: Raghupathi
authors.initials: R
authors.lastname: Neelarapu
authors.forename: Denise L
authors.initials: DL
authors.lastname: Holzle
authors.forename: Subash
authors.initials: S
authors.lastname: Velaparthi
authors.forename: He
authors.initials: H
authors.lastname: Bai
authors.forename: Michael
authors.initials: M
authors.lastname: Brunsteiner
authors.forename: Sylvie Y
authors.initials: SY
authors.lastname: Blond
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007555:Isoxazoles; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D018696:Neuroprotective Agents; D019920:Photoaffinity Labels; D011720:Pyrazoles; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C561227:octanedioic acid (1-(3-azido-5-azidomethylbenzyl)-1H-pyrazol-4-yl)amide hydroxyamide; C409470:HDAC8 protein, human