title: Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors.
abstract: A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.
authors.affiliation: Departments of Medicinal Chemistry and Molecular Biology, MethylGene Inc., 7220 Frederick-Banting, Montréal, Québec H4S 2A1, Canada.
authors.forename: Soon Hyung
authors.initials: SH
authors.lastname: Woo
authors.forename: Sylvie
authors.initials: S
authors.lastname: Frechette
authors.forename: Elie
authors.initials: E
authors.lastname: Abou Khalil
authors.forename: Giliane
authors.initials: G
authors.lastname: Bouchain
authors.forename: Arkadii
authors.initials: A
authors.lastname: Vaisburg
authors.forename: Naomy
authors.initials: N
authors.lastname: Bernstein
authors.forename: Oscar
authors.initials: O
authors.lastname: Moradei
authors.forename: Silvana
authors.initials: S
authors.lastname: Leit
authors.forename: Martin
authors.initials: M
authors.lastname: Allan
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Trachy-Bourget
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Daniel
authors.initials: D
authors.lastname: Delorme
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011994:Recombinant Proteins; C012589:trichostatin A