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-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.
Usera
Aimee R
AR
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA.
Dolan
Patrick M
PM
Kensler
Thomas W
TW
Posner
Gary H
GH
D000818:Animals; D002117:Calcitriol / Q000737:chemistry*; D002118:Calcium / Q000652:urine; D049109:Cell Proliferation / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry*; D015394:Molecular Structure; D051381:Rats; D013450:Sulfones / Q000737:chemistry*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D013450:Sulfones; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D005461:Fluorine; D002117:Calcitriol; D002118:Calcium