The synthesis and activity in vitro of 25-masked-1α-hydroxylated vitamin D3 analogs

Joseph L. Napoli*, Mary A. Fivizzani, Alan H. Hamstra, Heinrich K. Schnoes, Hector F. DeLuca, Paula H. Stern

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

1α-Hydroxylated-25-masked-vitainin D3 analogs were synthesized as probes to help evaluate the role of 25-hydroxyl group in hormone-receptor Interactions of 1α,25-dihydroxyvitamin D3 (13a). Synthetic work on model systems showed that the steroidal 25-hydroxyl group could be easily fluorinated in high yield with diethylaminosulfur trifluoride. Treatment of 25-fluoro compound with acetic acid resulted in both elimination and displacement of fluorine by acetate. The desired 1α-hydroxy-25-fluoro-vitamin D3 (14b) was obtained efficiently by fluorination and subsequent deacecylation of 1α,25-dihydroxyvitamin D3 1,3-diacetate (13b). Also obtained was a mixture of 1α-hydroxyvitamin D3-24- and 25-enes (15b). Both 14b and 15b were 300-400 times less active than 13a in the chick intestinal cytosol protein binding assay, making these analogs similar in potency to 1α-hydroxyvitamin D3 in vitro. The essentially equivalent activity of 14b and 15b with 1α-hydroxyvitamin D3 indicates that in the absence of a 25-hydroxyl group some alterations to the side chain carbons of 13a may be tolerated without further weakening analog-protein interactions. The fluoroanalog 14b was also about 250 times less potent than 13a in stimulating bone resorption in vitro. These compounds should prove to be valuable tools in aiding understanding of the salient structural features of the vitamin D3 metabolites.

Original languageEnglish (US)
Pages (from-to)453-466
Number of pages14
JournalSteroids
Volume32
Issue number4
DOIs
StatePublished - Nov 1978

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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