Conceptually new sulfone analogues of the hormone 1alpha, 25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation.
A conceptually new series of vitamin D(3)-like nonfluorinated and fluorinated 16-ene side chain tert-butyl sulfones 3-7 has been synthesized. Even though these novel C,D-ring side chain analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) (1,1,25D(3)) lack a terminal OH group, thought previously to be essential for high biological activity, they are highly antiproliferative and, in several cases, transcriptionally active in vitro but desirably noncalcemic in vivo. The side chain sulfone group may be binding to the nVDR as a hydrogen-bond acceptor, in contrast to the hydrogen-bond donor function of the 25-OH group of natural 1,25D(3).
Posner
G H
GH
Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Wang
Q
Q
Han
G
G
Lee
J K
JK
Crawford
K
K
Zand
S
S
Brem
H
H
Peleg
S
S
Dolan
P
P
Kensler
T W
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry; D002118:Calcium / Q000097:blood / Q000652:urine; D002455:Cell Division / Q000187:drug effects; D017611:Fluorine Compounds / Q000138:chemical synthesis; D006860:Hydrogen Bonding; D015603:Keratinocytes; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017611:Fluorine Compounds; D018167:Receptors, Calcitriol; D013450:Sulfones; D002117:Calcitriol; D002118:Calcium