Synthesis and biological evaluation of calcioic acid

Herein, we describe the synthesis of calcioic acid following a recently developed synthetic strategy for calcitroic acid. Several improvements to reaction conditions were made, which resulted in higher yields. The improved workup and isolation procedures are described. Furthermore, we investigated the interaction between the vitamin D receptor (VDR) and calcioic acid. Calcioic acid was able to bind VDR with a binding constant of 71 µM. In cells, calcioic acid reduced the transcription of VDR target gene CYP24A1 in the presence 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) but did not induce the transcription of CYP24A1. Therefore, calcioic acid is a very weak VDR antagonist. With the generation of gram quantities, further studies are expected to reveal if calcioic acid is solely a water-soluble metabolite of vitamin D or if it mediates other biological functions through biomolecules other than VDR.