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

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

doi:10.1021/jm801365a

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

J Med Chem. 2009 Apr 23;52(8):2204-13. doi: 10.1021/jm801365a.

Authors

Gilles Laverny¹, Giuseppe Penna, Milan Uskokovic, Stanislaw Marczak, Hubert Maehr, Pawel Jankowski, Caroline Ceailles, Paul Vouros, Brenden Smith, Matthew Robinson, G Satyanarayana Reddy, Luciano Adorini

Affiliation

¹ BioXell, 20132 Milan, Italy.

PMID: 19309155
DOI: 10.1021/jm801365a

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

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Antimicrobial Cationic Peptides / biosynthesis
Antimicrobial Cationic Peptides / genetics
Calcitriol / analogs & derivatives*
Calcitriol / chemical synthesis
Calcitriol / chemistry
Calcitriol / metabolism
Calcitriol / pharmacology
Calcium / blood*
Cathelicidins
Cell Line, Tumor
Cells, Cultured
Cytokines / antagonists & inhibitors
Humans
Immunologic Factors / chemical synthesis
Immunologic Factors / chemistry
Immunologic Factors / metabolism
Immunologic Factors / pharmacology
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Mice
Mice, Inbred C57BL
Molecular Structure
Rats
Receptors, Calcitriol / physiology
Steroid Hydroxylases / biosynthesis
Steroid Hydroxylases / genetics
Structure-Activity Relationship
Vitamin D3 24-Hydroxylase

Substances

1,25-dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3
1,25-dihydroxy-16-ene-20-cyclopropylvitamin D3
Anti-Inflammatory Agents, Non-Steroidal
Antimicrobial Cationic Peptides
Cathelicidins
Cytokines
Immunologic Factors
Receptors, Calcitriol
Steroid Hydroxylases
CYP24A1 protein, human
Cyp24a1 protein, mouse
Cyp24a1 protein, rat
Vitamin D3 24-Hydroxylase
Calcitriol
Calcium