title: Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors.
abstract: In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4-dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40-fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC(50) values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.
authors.affiliation: MethylGene Inc, Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, Que., Canada H4S 2A1. smild@methylgene.com
authors.forename: David V
authors.initials: DV
authors.lastname: Smil
authors.forename: Sukhdev
authors.initials: S
authors.lastname: Manku
authors.forename: Yves A
authors.initials: YA
authors.lastname: Chantigny
authors.forename: Silvana
authors.initials: S
authors.lastname: Leit
authors.forename: Amal
authors.initials: A
authors.lastname: Wahhab
authors.forename: Theresa P
authors.initials: TP
authors.lastname: Yan
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Christiane
authors.initials: C
authors.lastname: Maroun
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lemieux
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolescu
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Anthony
authors.initials: A
authors.lastname: Panetta
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Robert
authors.initials: R
authors.lastname: Déziel
mesh_terms: D000107:Acetylation; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D020033:Protein Isoforms; D014404:Tubulin / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010879:Piperazines; D020033:Protein Isoforms; D014404:Tubulin; D000077489:Piperazine; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases