TY - JOUR
T1 - 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
AU - Laverny, Gilles
AU - Penna, Giuseppe
AU - Uskokovic, Milan
AU - Marczak, Stanislaw
AU - Maehr, Hubert
AU - Jankowski, Pawel
AU - Ceailles, Caroline
AU - Vouros, Paul
AU - Smith, Brenden
AU - Robinson, Matthew
AU - Reddy, G. Satyanarayana
AU - Adorini, Luciano
PY - 2009/4/23
Y1 - 2009/4/23
N2 - 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.
AB - 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.
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U2 - 10.1021/jm801365a
DO - 10.1021/jm801365a
M3 - Article
C2 - 19309155
AN - SCOPUS:65249116273
VL - 52
SP - 2204
EP - 2213
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -