title: Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1alpha,25-dihydroxyvitamin D3.
abstract: A series 2a-4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a.
authors.affiliation: Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA. ghp@jhu.edu
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kahraman
authors.forename: Heung Bae
authors.initials: HB
authors.lastname: Jeon
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Suh
authors.forename: Hongbin
authors.initials: H
authors.lastname: Li
authors.forename: Patrick
authors.initials: P
authors.lastname: Dolan
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
mesh_terms: D000818:Animals; D002118:Calcium / Q000652:urine; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015603:Keratinocytes / Q000187:drug effects*; D007659:Ketones / Q000737:chemistry*; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C116441:2-methyl-1,25-dihydroxyvitamin D3; D007659:Ketones; D014807:Vitamin D; D002118:Calcium