title: Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors.
abstract: A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and alpha-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cincinelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Nannei
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Morini
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Marcella
authors.initials: M
authors.lastname: Barbarino
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; D016159:Tumor Suppressor Protein p53