Practical synthesis and evaluation of the biological activities of 1alpha,25-dihydroxyvitamin D3 antagonists, 1alpha,25-dihydroxyvitamin D3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis

J Med Chem. 2006 Apr 20;49(8):2398-406. doi: 10.1021/jm050738x.

Abstract

A practical synthetic route to novel vitamin D antagonists of DLAM (1alpha,25-dihydroxyvitamin D(3)-26,23-lactam) was developed from vitamin D(2) via the 1,3-dipolar cycloaddition reaction as a key step. Six DLAM derivatives (24 compounds) with a variety of nitrogen substituents and stereochemistries at C23 and C25 were synthesized. Among these new derivatives, (23S,25S)-DLAM isomers bound effectively to VDRs and showed antagonistic activity in the HL-60 cell differentiation inhibition assay. The importance of the substituent on the nitrogen of DLAMs for antagonistic activity was also suggested by computational docking studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Calcitriol / analogs & derivatives*
  • Calcitriol / antagonists & inhibitors*
  • Calcitriol / chemical synthesis
  • Calcitriol / chemistry
  • Calcitriol / pharmacology
  • Cell Differentiation / drug effects
  • Chlorocebus aethiops
  • Computational Biology
  • Crystallography, X-Ray
  • Drug Design
  • HL-60 Cells
  • Humans
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Protein Structure, Secondary
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vitamin D / analogs & derivatives*
  • Vitamin D / antagonists & inhibitors*
  • Vitamin D / chemistry

Substances

  • DLAM-1P compound
  • Lactams
  • Vitamin D
  • Calcitriol