title: Synthesis of rigid trichostatin A analogs as HDAC inhibitors.
abstract: New inhibitors of histone deacetylase (HDAC) have been synthesized and evaluated for their activity toward non small lung cancer cell line H661. Their design is based on indanone (or tetralone) systems leading to trichostatin A (TSA) analogs with limited conformational mobility. Molecular modelization at the AM1 level revealed that the conformations of indane-based analogs and TSA bound to HDAC like protein are similar. The synthesis of these new analogs was achieved by alkylation of an appropriate indanone (or tetralone) to introduce the side chain bearing a terminal ester group, the latter being a precursor of hydroxamic acid and aminobenzamide derivatives. Hydroxamic acids with the TSA side chain were found to be the most active compounds and the presence of the dimethylamino group on the phenyl ring turned out to be essential to achieve low micromolar activities against H661 cancer cells.
authors.affiliation: Laboratoire Synthèse et Réactivité des Substances Naturelles, UMR 6514, Université de Poitiers et CNRS, 40 Avenue du Recteur Pineau, 86022 Poitiers, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Charrier
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertrand
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gesson
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roche
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A