title: New derivatives of 1alpha,25-dihydroxy-19-norvitamin D3 with two substituents at C-2: synthesis and biological activity.
abstract: To examine the effect of 2,2-disubstitution on the biological activities of 19-norvitamin D analogs, novel 2,2-disubstituted-(20R)- and (20S)-1alpha,25-dihydroxy-19-norvitamin D3 analogs were prepared and their biological activities were studied. All the synthesized analogs possessing hydrophobic 2alpha-substituents were more active than the corresponding 2beta-isomers both in binding to the vitamin D receptor and in activating gene transcription. The 2alpha-methyl-2beta-hydroxy analog 9b was found to have markedly higher transcriptional activity (32-fold) than the natural ligand 1a, although the two had the same binding affinity to the vitamin D receptor. To our knowledge, this analog is among the most potent of 19-norvitamin D analogs.
authors.affiliation: Laboratory of Medicinal Chemistry, School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. shimizu.mr@tmd.ac.jp
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Mika
authors.initials: M
authors.lastname: Shimazaki
authors.forename: Youhei
authors.initials: Y
authors.lastname: Amano
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reischl
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007536:Isomerism; D008024:Ligands; D008968:Molecular Conformation; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol