Effects of fluorines on nonsecosteroidal vitamin D receptor agonists

From our research of nonsecosteroidal vitamin D₃ derivatives with gamma hydroxy carboxylic acid, we identified compound 6, with two CF₃ groups in the side chain, as a most potent vitamin D receptor (VDR) agonist that shows superagonistic activity in VDRE reporter gene assay, MG-63 osteocalcin production assay and HL-60 cell differentiation assay. Compound 6 demonstrated that fluorination is as effective in the case of our nonsecosteroidal scaffold as in the case of secosteroidal VD₃ analogs. X-ray analysis of the VDR with compound 6 revealed all of the six fluorine atoms of the hexafluoropropanol (HFP) moiety in the side chain effectively interacting with the VDR by both steric (van der Waals) and electrostatic (hydrogen bond, NH–F and CH–F) interactions. The HFP moiety of 6 effectively interacts with helix 12 (H12) of the VDR and stabilizes the position and the orientation of H12, which could result in stabilizing the coactivator and enhancing the VDR agonistic activity.