Calcitriol derivatives with two different side chains at C-20. 24-hydroxy derivatives as metabolic products and molecular probes for VDR exploration.
We previously synthesized calcitriol derivatives with two identical side chains emanating at C-20, also known as gemini. In view of the evidence identifying C-24 hydroxylation as the first step in the in the metabolic cascade of calcitriol and gemini, stereochemical differentiation between the possible epimeric 20R- and 20S side-chain hydroxylated gemini became of interest. We now report the stereoselective synthesis of these compounds. Of these, 1,24(R),25-trihydroxy-21-(3-hydroxy-3-methyl-butyl)-20(R)-19-nor-cholecalciferol was identified as the main metabolic product of 19-nor-gemini. In general, higher doses of the 24-hydroxylated gemini compounds were required to increase blood calcium levels in mice and to suppress INF-gamma release in MLR.
Maehr
Hubert
H
Bioxell Inc., 340 Kingsland Street, Bldg. 76/13, Nutley, NJ 07110, USA. hubert.maehr@roche.com
Uskokovic
Milan R
MR
Reddy
G Satyanarayana
GS
Adorini
Luciano
L
D000818:Animals; D002117:Calcitriol / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D015335:Molecular Probes; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism
D015335:Molecular Probes; D018167:Receptors, Calcitriol; D002117:Calcitriol