Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antimicrobial Cationic Peptides / biosynthesis
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Antimicrobial Cationic Peptides / genetics
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Calcitriol / analogs & derivatives*
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Calcitriol / chemical synthesis
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Calcitriol / chemistry
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Calcitriol / metabolism
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Calcitriol / pharmacology
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Calcium / blood*
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Cathelicidins
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Cell Line, Tumor
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Humans
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Immunologic Factors / chemical synthesis
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Immunologic Factors / chemistry
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Immunologic Factors / metabolism
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Immunologic Factors / pharmacology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Mice
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Mice, Inbred C57BL
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Molecular Structure
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Rats
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Receptors, Calcitriol / physiology
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Steroid Hydroxylases / biosynthesis
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Steroid Hydroxylases / genetics
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Structure-Activity Relationship
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Vitamin D3 24-Hydroxylase
Substances
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1,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3
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1,25-dihydroxy-16-ene-20-cyclopropylvitamin D3
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Anti-Inflammatory Agents, Non-Steroidal
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Antimicrobial Cationic Peptides
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Cathelicidins
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Cytokines
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Immunologic Factors
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Receptors, Calcitriol
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Steroid Hydroxylases
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CYP24A1 protein, human
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Cyp24a1 protein, mouse
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Cyp24a1 protein, rat
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Vitamin D3 24-Hydroxylase
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Calcitriol
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Calcium