title: Methyl-introduced A-ring analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and biological evaluation.
abstract: The hormonally-active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1), has a wide variety of biological activities, which makes it a promising therapeutic agent for the treatment of cancer, psoriasis and osteoporosis. Insights into the structure-activity relationships of the A-ring of 1 are needed to assist the development of more potent and selective analogues, as well as to define the molecular mode of action. All possible A-ring stereoisomers of 2-methyl-1,25-dihydroxyvitamin D3 and 2,2-dimethyl-1,25-dihydroxyvitamin D3, which differ in stereochemistry at the C1-, C2- and C3-positions, were designed and efficiently synthesized by employing the convergent method. Biological evaluation of the analogues, in terms of the vitamin D receptor-binding affinity and HL-60 cell differentiation-inducing activity, as well as the transcriptional potency in ROS 17/2.8 cells, revealed the importance of substituents at the C2-position in certain orientations.
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa 769-2193, Japan. tofu@kph.bunri-u.ac.jp
authors.forename: Toshie
authors.initials: T
authors.lastname: Fujishima
authors.forename: Ryuji
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Negishi
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol