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.

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
  • ropocamptide
  • Steroid Hydroxylases
  • CYP24A1 protein, human
  • Cyp24a1 protein, mouse
  • Cyp24a1 protein, rat
  • Vitamin D3 24-Hydroxylase
  • Calcitriol
  • Calcium