Calcitriol derivatives with two different side chains at C-20. 24-hydroxy derivatives as metabolic products and molecular probes for VDR exploration |
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Authors: | Maehr Hubert Uskokovic Milan R Reddy G Satyanarayana Adorini Luciano |
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Institution: | Bioxell Inc., 340 Kingsland Street, Bldg. 76/13, Nutley, NJ 07110, USA. hubert.maehr@roche.com |
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Abstract: | 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. |
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