Antiproliferative, low-calcemic, fluorinated sulfone analogs of 1alpha,25-dihydroxyvitamin D3: chemical synthesis and biological evaluation

Novel fluorinated sulfone analogs of the hormone 1alpha,25-dihydroxyvitamin D(3) have been designed and synthesized in order to study the biological effects of fluorine incorporation at the terminus of the C,D-ring side chain. Although biologically active 26,27-hexafluorinated 1alpha,25-dihydroxyvit...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2007-08, Vol.15 (16), p.5509-5518
Main Authors: Usera, Aimee R, Dolan, Patrick M, Kensler, Thomas W, Posner, Gary H
Format: Article
Language:English
Subjects:
Animals
Calcitriol - chemistry
Calcium - urine
Cell Proliferation - drug effects
Fluorine - chemistry
Molecular Structure
Rats
Sulfones - chemistry
Vitamin D - analogs & derivatives
Vitamin D - chemical synthesis
Vitamin D - chemistry
Vitamin D - pharmacology
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Summary:Novel fluorinated sulfone analogs of the hormone 1alpha,25-dihydroxyvitamin D(3) have been designed and synthesized in order to study the biological effects of fluorine incorporation at the terminus of the C,D-ring side chain. Although biologically active 26,27-hexafluorinated 1alpha,25-dihydroxyvitamin D(3) analogs have been synthesized previously, this investigation reports the first successful fluorinated series in which trifluoromethyl sulfone analogs present a favorable biological profile. This study shows that two new analogs featuring incorporation of a synthetically simple single trifluoromethyl sulfone group have significantly increased antiproliferative activity while causing desirably low in vivo calciuria relative to that of calcitriol. Incorporation of additional fluorines, as in a perfluorobutyl analog, results in a loss of antiproliferative activity.
ISSN:0968-0896