title: 13-Methyl-substituted des-C,D analogs of (20S)-1alpha,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD): synthesis and biological evaluation.
abstract: Analogs of (20S)-1alpha,25-dihydroxy-2-methylene-19-norvitamin D(3) (2, 2MD), substituted at C-13 but lacking both C and D rings, were prepared in convergent syntheses, starting with the chiral ester 14 and the phosphine oxide 29. Two of the synthesized vitamins (11 and 32) were analogs in which the 13-methyl group constituted a substituent of an unsaturated fragment, that is, C(13)-C(17) double bond, whereas in the two other cases (12 and 13), the methyl group belonged to a ternary carbon stereogenic center. The aim of these studies was to further explore extensive modifications in the 'upper' part of the vitamin D skeleton in the hope of finding biologically active analogs of potential therapeutic value. The commercial (R)-(-)-methyl-3-hydroxy-2-methylpropionate (14) was converted in six steps to alcohol 18, the vitamin D side chain fragment. Its subsequent three-step transformation led to aldehyde 20 which was subjected to the Still-Gennari HWE reaction with anion derived from ester 21. The obtained alpha,beta-unsaturated esters 22 and 23 served as convenient starting compounds to the syntheses of the corresponding chiral acyclic aldehydes, beta,gamma-unsaturated (28) and saturated (39 and 40), required for the final Wittig-Horner coupling with the anion of the phosphine oxide 29. After hydroxyl deprotection, the synthesized vitamin D analogs 11-13 and 32 were purified and biologically tested. Only the (13R,20S)-analog 12 retained substantial, although 30 times lower than 1alpha,25-(OH)(2)D(3), binding ability to the full-length rat recombinant vitamin D receptor (VDR). This analog was also very effective in differentiation of HL-60 cells, and it exerted significant transcriptional activity (2 times and 15 times less potent, respectively, as compared to the native hormone). The in vivo tests showed that all synthesized vitamin D analogs were devoid of calcemic activity.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Plonska-Ocypa
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Pawel
authors.initials: P
authors.lastname: Grzywacz
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Frelek
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C468519:2-methylene-1,25-dihydroxy-19-norvitamin D3; D018167:Receptors, Calcitriol; D002117:Calcitriol