title: Synthesis, structure, and biological activity of des-side chain analogues of 1α,25-dihydroxyvitamin D3 with substituents at C18.
abstract: An improved synthetic route to 1α,25-dihydroxyvitamin D(3) des-side chain analogues 2 a and 2 b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitamin D receptor (hVDR) complexed to one of these analogues, 20(17→18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D(3) (2 a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D(3).
authors.affiliation: Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Paloma
authors.initials: P
authors.lastname: Ordóñez-Morán
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Larriba
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sato
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Miguel
authors.initials: M
authors.lastname: Maestro
authors.forename: Samuel
authors.initials: S
authors.lastname: Seoane
authors.forename: Fernando
authors.initials: F
authors.lastname: Dominguez
authors.forename: Silvina
authors.initials: S
authors.lastname: Eduardo-Canosa
authors.forename: Daniel
authors.initials: D
authors.lastname: Nicoletti
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Moman
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
mesh_terms: D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013552:Swine
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol