Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs

Abstract Vitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 , 1 ), is a promising target for multiple clinical applications. We recently developed non-secosteroidal VDR ligands based on a carbon-containing boron cluster, 1,12-dicarba- closo -dodecaborane ( p -carborane), and examined the binding of one of them to VDR by means of crystallographic analysis. Here, we utilized that X-ray structure to design novel p -carborane-based tetraol-type vitamin D analogs, and we examined the biological activities of the synthesized compounds. Structure–activity relationship study revealed that introduction of an ω-hydroxyalkoxy functionality enhanced the biological activity, and the configuration of the substituent significantly influenced the potency. Among the synthesized compounds, 4-hydroxybutoxy derivative 9a exhibited the most potent activity, which was equal to that of the secosteroidal vitamin D analog, 19- nor -1α,25-dihydroxyvitamin D 3 ( 2 ).