Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1alpha,25-dihydroxyvitamin D3.
A series 2a-4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a.
Posner
Gary H
GH
Department of Chemistry, The Johns Hopkins University, Baltimore, MD 21218, USA. ghp@jhu.edu
Kim
Hyung Jin
HJ
Kahraman
Mehmet
M
Jeon
Heung Bae
HB
Suh
Byung Chul
BC
Li
Hongbin
H
Dolan
Patrick
P
Kensler
Thomas W
TW
D000818:Animals; D002118:Calcium / Q000652:urine; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015603:Keratinocytes / Q000187:drug effects*; D007659:Ketones / Q000737:chemistry*; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C116441:2-methyl-1,25-dihydroxyvitamin D3; D007659:Ketones; D014807:Vitamin D; D002118:Calcium