@article {290, title = {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.}, journal = {Journal of Medicinal Chemistry}, volume = {45}, year = {2002}, month = {2002 Aug 1}, pages = {3366-80}, abstract = {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{\textquoteright}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.}, keywords = {Animals, Binding Sites, Biological Transport, Calcitriol, Calcium, Cell Differentiation, Chromatography, High Pressure Liquid, HL-60 Cells, Humans, Intestinal Mucosa, Ligands, Magnetic Resonance Spectroscopy, Male, Models, Molecular, Molecular Conformation, Rats, Receptors, Calcitriol, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Swine}, issn = {0022-2623}, author = {Rafal R. Sicinski and Piotr Rotkiewicz and Andrzej Koli{\'n}ski and Wanda Sicinska and Jean M. Prahl and Connie M. Smith and Hector F. DeLuca} }