Design, synthesis, and properties of des-D-ring interphenylene derivatives of 1α,25-Dihydroxyvitamin D3

Abstract

Novel des-D-ring interphenylene analogs of vitamin D₃ were designed on the basis of their conformational analysis and affinity to vitamin D receptor (VDR) estimated using ligand-protein docking simulation. According to this design, a series of the des-D-ring interphenylene analogs were synthesized via Suzuki-Miyaura coupling reactions of des-D, C-ring and A-ring intermediates. A fluorescence polarization VDR competitor assay, a time-resolved fluorescence resonance energy transfer VDR coactivator binding assay, and a human VDR (NR1I1) reporter assay revealed that the des-D-ring interphenylene analogs exhibited a certain VDR binding affinity and ability to promote gene transcription. In particular, analogs having a side chain with an appropriate length at meta position showed high gene transcription promoting activities comparable to those of 1α,25-dihydroxyvitamin D₃ and its 19-nor derivative.

Keywords: Des-D-ring; Reporter gene assay; Suzuki-Miyaura coupling; Vitamin D receptor; Vtamin D analog; s.