Synthesis and anti-inflammatory properties of 1 α,25-dihydroxy-16- ene-20-cyclopropyl-24-oxo-vitamin d 3, a hypocalcemic, stable metabolite of 1α,25-dihydroxy-16-ene-20-cyclopropylvitamin D 3

Gilles Laverny, Giuseppe Penna, Milan Uskokovic, Stanislaw Marczak, Hubert Maehr, Pawel Jankowski, Caroline Ceailles, Paul Vouros, Brenden Smith, Matthew Robinson, G. Satyanarayana Reddy, Luciano Adorini

Research output: Contribution to journalArticle

Abstract

1α,25(OH) 2-16-ene-20-cyclopropyl-vitamin D 3 (13) is several fold more potent than the natural hormone 1α,25- dihydroxyvitamin D 3 (1) as an anti-inflammatory agent. Here, we have further analyzed the antiinflammatory properties of 13, confirming it as the most potent analogue tested within this family. We then determined the structures of all the natural metabolites of 13, including the 24-oxo metabolite 14, and carried out its synthesis. A comparison of 13 with 14 showed a similar induction of the primary VDR target genes CYP24A1 and CAMP and comparable anti-inflammatory properties as revealed by a similar inhibition of TNF-α, IL-12/23p40, IL-6, and IFN-γ production. Interestingly, 14 displays a 3-fold lower calcemic activity in vivo compared to 13. Collectively, these findings indicate that the strong potency of 13 can be explained by the accumulation of its stable 24-oxo metabolite, which shows immunoregulatory and anti-inflammatory properties superimposable to those exerted by 13 itself.

Original languageEnglish
Pages (from-to)2204-2213
Number of pages10
JournalJournal of Medicinal Chemistry
Volume52
Issue number8
DOIs
Publication statusPublished - Apr 23 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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