Synthesis and anti-inflammatory properties of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a hypocalcemic, stable metabolite of 1alpha,25-dihydroxy-16-ene-20-cyclopropyl-vitamin D3.
1alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D(3) (13) is several fold more potent than the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1) as an anti-inflammatory agent. Here, we have further analyzed the anti-inflammatory 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-alpha, IL-12/23p40, IL-6, and IFN-gamma 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.
Laverny
Gilles
G
BioXell, 20132 Milan, Italy.
Penna
Giuseppe
G
Uskokovic
Milan
M
Marczak
Stanislaw
S
Maehr
Hubert
H
Jankowski
Pawel
P
Ceailles
Caroline
C
Vouros
Paul
P
Smith
Brenden
B
Robinson
Matthew
M
Reddy
G Satyanarayana
GS
Adorini
Luciano
L
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood*; D054804:Cathelicidins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D051381:Rats; D018167:Receptors, Calcitriol / Q000502:physiology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D065668:Vitamin D3 24-Hydroxylase
C540328:1,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3; C540327:1,25-dihydroxy-16-ene-20-cyclopropylvitamin D3; D000894:Anti-Inflammatory Agents, Non-Steroidal; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D016207:Cytokines; D007155:Immunologic Factors; D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; C585551:Cyp24a1 protein, rat; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium