Retiferols - synthesis and biological activity of a conceptually novel class of vitamin D analogs

The hypothesis that retiferols are a novel class of vitamin D analogs with therapeutic potential has been recently proved. The CD-ring of vitamin D, originated from a steroid precursor, is not necessary for biological activity. The retiferol, disubstituted at C-13, was bound to the ligand-binding domain (LBD) of vitamin D receptor (VDR) just like the vitamin D hormone [1,25-(OH)2D3]. This finding opens the way for retiferols as a novel class of vitamin D therapeutics.

This review presents the concept of retiferols and their structure evolution. Medicinal chemistry and therapeutic perspective of retiferols are reviewed showing how these vitamin D analogs became a source of potential therapeutics.

Docking experiments and molecular modeling have shown that positioning of vitamin D analog at the LBD of VDR is not disturbed by deletion of a large portion of the vitamin D, exactly as hypothesized. Twenty years of structural modifications have shown that removal of the CD-ring fragment and regioselective methylation results in an almost complete loss of the undesired calcemic activity of retiferol while gaining the agonistic activity comparable to that of 1,25-(OH)2D3.