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

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 hydro...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-08, Vol.45 (16), p.3366-3380
Main Authors: Sicinski, Rafal R, Rotkiewicz, Piotr, Kolinski, Andrzej, Sicinska, Wanda, Prahl, Jean M, Smith, Connie M, DeLuca, Hector F
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Biological Transport - drug effects
Calcitriol - analogs & derivatives
Calcitriol - chemical synthesis
Calcitriol - chemistry
Calcitriol - pharmacology
Calcium - metabolism
Cell Differentiation - drug effects
Chromatography, High Pressure Liquid
HL-60 Cells
Humans
In Vitro Techniques
Intestinal Mucosa - metabolism
Ligands
Magnetic Resonance Spectroscopy
Male
Models, Molecular
Molecular Conformation
Rats
Receptors, Calcitriol - chemistry
Receptors, Calcitriol - metabolism
Spectrophotometry, Ultraviolet
Structure-Activity Relationship
Swine
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Summary: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.
ISSN:0022-2623