TY - JOUR T1 - 2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor JF - The Journal of Steroid Biochemistry and Molecular Biology Y1 - 2004 A1 - Pawel Grzywacz A1 - Lori A. Plum A1 - Wanda Sicinska A1 - Rafal R. Sicinski A1 - Jean M. Prahl A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Calcitriol KW - Female KW - HL-60 Cells KW - Humans KW - Hydrocarbons KW - Ligands KW - Methane KW - Mice KW - Models, Molecular KW - Rats KW - Receptors, Calcitriol AB - In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported. VL - 89-90 IS - 1-5 ER -