title: Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains.
abstract: Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.
authors.affiliation: Departamento de Química Orgánica, Universidad de Santiago y Unidad Asociada al CSIC, Avda de las Ciencias s/n, 15782 Santiago de Compostela, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Fraga
authors.forename: Flavia
authors.initials: F
authors.lastname: Zacconi
authors.forename: Fredy
authors.initials: F
authors.lastname: Sussman
authors.forename: Paloma
authors.initials: P
authors.lastname: Ordóñez-Morán
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Huet
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Molnár
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Miguel
authors.initials: M
authors.lastname: Maestro
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D005663:Furans; D018167:Receptors, Calcitriol; D014807:Vitamin D; C039281:furan