title: Design, synthesis and evaluation of antiestrogen and histone deacetylase inhibitor molecular hybrids.
abstract: The combination of antiestrogens and histone deacetylase inhibitors (HDACi) has been found to be antiproliferative in breast cancer models. We designed and synthesized hybrid structures which combined structural features of the pure antiestrogen ICI-164,384 and HDACi's SAHA and entinostat in a single bifunctional molecule. The hybrids retained antiestrogenic and HDACi activity and, in the case of benzamide hybrids, were selective for Class I HDAC3 over Class II HDAC6. The hybrids possessed low micromolar to high nanomolar activity against both ER+ MCF-7 and ER- MDA-MB-231 breast cancer cell models.
authors.affiliation: Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Mendoza-Sanchez
authors.affiliation: Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Cotnoir-White
authors.affiliation: Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
authors.forename: Justyna
authors.initials: J
authors.lastname: Kulpa
authors.affiliation: Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada.
authors.forename: Isabel
authors.initials: I
authors.lastname: Jutras
authors.affiliation: Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Pottel
authors.affiliation: Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
authors.affiliation: Institute for Research in Immunology and Cancer, Pavillon Marcelle-Coutu, Université de Montréal, 2950 chemin de Polytechnique, Montréal, Québec H3T 1J4, Canada. Electronic address: sylvie.mader@umontreal.ca.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mader
authors.affiliation: Department of Chemistry, Otto Maass Building, McGill University, 801 Sherbrooke Street West, Montreal, Québec H3A 0B8, Canada. Electronic address: jim.gleason@mcgill.ca.
authors.forename: James L
authors.initials: JL
authors.lastname: Gleason
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D000099186:Histone Deacetylase 3; C118739:entinostat; C051781:ICI 164384
keywords: Antiestrogens; Breast cancer; Estrogen receptor; HDACi