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Calcitriol derivatives with two different side chains at C-20. II. Diastereoselective syntheses of the metabolically produced 24(R)-hydroxygemini.

Maehr H, Uskokovic MR, Adorini L, Reddy GS

Bioxell, Inc., Nutley, New Jersey 07110, USA. Hubert.maehr@roche.com

Vitamin D derivatives containing two side chains emanating at C-20 are known as gemini. We have recently synthesized two gemini which are related to calcitriol and 19-norcalcitriol containing two identical side chains. The metabolism of these species involves 24(R)-hydroxylation on one of the side chains. To determine the outcome of this diastereospecific transformation, we synthesized both C-20 epimeric pairs containing the 24(R)-hydroxy group in the gemini and 19-norgemini series. On the basis of the availability of these reference compounds, it was shown that the metabolic hydroxylation occurred at the pro-R side chain in both gemini compounds. In comparison to the parent compounds, the 24-hydroxygemini required higher doses to increase blood calcium levels in mice and to suppress INF-gamma release in MLR.

Published 13 December 2004 in J Med Chem, 47(26): 6476-84.
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