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 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.
Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
Rafal R
RR
Sicinski
Piotr
P
Rotkiewicz
Andrzej
A
Kolinski
Wanda
W
Sicinska
Jean M
JM
Prahl
Connie M
CM
Smith
Hector F
HF
DeLuca
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013552:Swine
D008024:Ligands; D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol; D002118:Calcium