Synthesis of 1alpha,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), a novel series of 1 alpha,25-dihydroxyvitamin D3 antagonist

Bioorg Med Chem Lett. 2004 May 17;14(10):2579-83. doi: 10.1016/j.bmcl.2004.02.076.

Abstract

Novel vitamin D(3) analogs having a lactam structure in their side chains, 1 alpha,25-dihydroxyvitamin D(3)-26,23-lactams (DLAMs), were designed based on the principle of regulation of the folding of helix-12 in the vitamin D nuclear receptor (VDR). The new analogs were synthesized via 1,3-dipolar cycloaddition reaction and subsequent reduction of the isoxazolidine as key steps. Among the analogs, (23S,25S)-DLAM-01 (4a) and (23S,25S)-DLAM-1P (5a) bind strongly to VDR. Moreover, these analogs were found to inhibit the differentiation of HL-60 cells induced by 1 alpha,25-dihydroxyvitamin D(3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Drug Design
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Lactams / chemical synthesis*
  • Lactams / pharmacology
  • Protein Binding
  • Receptors, Calcitriol / chemistry
  • Receptors, Calcitriol / drug effects*
  • Structure-Activity Relationship
  • Vitamin D / analogs & derivatives*
  • Vitamin D / antagonists & inhibitors*
  • Vitamin D / chemical synthesis

Substances

  • Lactams
  • Receptors, Calcitriol
  • dihydroxy-vitamin D3
  • Vitamin D