title: 2,2-Disubstituted analogues of the natural hormone 1 alpha,25-dihydroxyvitamin D(3): chemistry and biology.
abstract: Six new 2,2-disubstituted analogues of the natural hormone calcitriol have been prepared. Chemical novelty includes (1) the first example of an inverse-electron-demand Diels-Alder cycloaddition using a pyrone diene and a difluorinated vinyl ether dienophile, leading to difluorinated analogues 7 and (2) a conceptually streamlined approach to dimethylated 19-nor analogues. Analogues 7a and are similar to calcitriol in terms of in vitro antiproliferative activity, but they are different from calcitriol in terms of transcriptional activity: difluorinated analogue 7a is 2-3 times more active transcriptionally than calcitriol, whereas dimethylated analogue is 7.5 times less active transcriptionally. Whereas the in vivo calcemic activity of difluorinated analogue 7a is similar to that of calcitriol, dimethylated analogue is considerably less calcemic than calcitriol. Dimethylated analogue strongly suppresses parathyroid hormone (PTH) secretion.
authors: Department of Chemistry, Krieger School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA. ghp@jhunix.hcf.jhu.edu
authors: Gary H
authors: GH
authors: Posner
authors: Benjamin T
authors: BT
authors: Woodard
authors: Kenneth R
authors: KR
authors: Crawford
authors: Sara
authors: S
authors: Peleg
authors: Alex J
authors: AJ
authors: Brown
authors: Patrick
authors: P
authors: Dolan
authors: Thomas W
authors: TW
authors: Kensler
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051381:Rats; D013057:Spectrum Analysis
chemical_list: D002117:Calcitriol