'Novel alkyl side chain sulfone 1alpha,25-dihydroxyvitamin D3 analogs: a comparison of in vitro antiproliferative activities and in vivo calcemic activities'.
The replacement of a t-butyl group with a trifluoromethyl group has profound effects on the biological profile of 1alpha,25-dihydroxyvitamin D(3) sulfone analogs. Investigation of whether the improved biological activities are due to steric and electronic factors of the trifluoromethyl group led to the design, synthesis and biological evaluation of two analogous alkyl sulfone molecules, methyl sulfone (AU-16-ene-25-SO(2)-CH(3)) and isopropyl sulfone (AU-16-ene-25-SO(2)-i-Pr). These alkyl sulfones are sterically comparable to, but electronically very different from a trifluoromethyl group. The syntheses, antiproliferative activities and calcemic activities of these new alkyl sulfones are presented herein. In comparing the in vitro antiproliferative profiles of the new alkyl sulfone 1alpha,25-dihydroxyvitamin D(3) analogs with the trifluoromethylsulfone and an analogous t-butyl sulfone, the activities increase in the following order: CH(3) < t-Bu approximately = i-Pr < CF(3). In contrast to the calcemic t-butyl sulfone, the novel alkyl sulfones and trifluoromethyl sulfone display desirable low calcemic levels.
Usera
Aimee R
AR
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, United States.
Dolan
Patrick
P
Kensler
Thomas W
TW
Posner
Gary H
GH
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015603:Keratinocytes / Q000166:cytology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D013450:Sulfones; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium