TY - JOUR T1 - 2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. JF - Journal of Medicinal Chemistry Y1 - 2002 A1 - Rafal R. Sicinski A1 - Piotr Rotkiewicz A1 - Andrzej KoliƄski A1 - Wanda Sicinska A1 - Jean M. Prahl A1 - Connie M. Smith A1 - Hector F. DeLuca KW - Animals KW - Binding Sites KW - Biological Transport KW - Calcitriol KW - Calcium KW - Cell Differentiation KW - Chromatography, High Pressure Liquid KW - HL-60 Cells KW - Humans KW - Intestinal Mucosa KW - Ligands KW - Magnetic Resonance Spectroscopy KW - Male KW - Models, Molecular KW - Molecular Conformation KW - Rats KW - Receptors, Calcitriol KW - Spectrophotometry, Ultraviolet KW - Structure-Activity Relationship KW - Swine AB - Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported. VL - 45 IS - 16 ER -