title: Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D₃ analogues with a long side chain at C12 and short C17 side chains.
abstract: Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D₃ bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a-c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen-Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization-Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D₃ analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D₃ but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.
authors.affiliation: Departamento de Química Orgánica y Unidad Asociada al CSIC, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Carballa
authors.forename: Samuel
authors.initials: S
authors.lastname: Seoane
authors.forename: Flavia
authors.initials: F
authors.lastname: Zacconi
authors.forename: Xenxo
authors.initials: X
authors.lastname: Pérez
authors.forename: Antonio
authors.initials: A
authors.lastname: Rumbo
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez-Díaz
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Larriba
authors.forename: Román
authors.initials: R
authors.lastname: Pérez-Fernández
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Miguel
authors.initials: M
authors.lastname: Maestro
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.forename: Mercedes
authors.initials: M
authors.lastname: Torneiro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015891:Cystatins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D015891:Cystatins; D018167:Receptors, Calcitriol; C071378:CST5 protein, human; D002117:Calcitriol; D002118:Calcium