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Paper | Special issue | Vol 103, No. 1, 2021, pp.444-458
Published online, 26th October, 2020
DOI: 10.3987/COM-20-S(K)30
Synthesis and Structure-Activity Relationship Study of 1,12-Dicarba-closo-dodecaborane-based Triol Derivatives as Nonsecosteroidal Vitamin D Analogs

Shinya Fujii, Ryota Sekine, Atsushi Kano, Hiroyuki Masuno, Emiko Kawachi, Tomoya Hirano, and Hiroyuki Kagechika*

*Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Surugadai, Kanda, Chiyoda-ku 101-0062, Japan

Abstract

The secosteroidal hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is a specific ligand of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are promising candidates for multiple clinical applications. We previously developed a series of 1,12-dicarba-closo-dodecaborane (p-carborane) derivatives as nonsecosteroidal VDR agonists. Here, we report the synthesis and structure-activity relationship of p-carborane-based nonsecosteroidal vitamin D analogs bearing a nitrogen or a sulfur atom in the linker structure. Biological evaluation revealed that the structure–activity relationships of amine derivatives and sulfide derivatives are different, and therefore the choice of the linker structure significantly affects the activity. We also found that benzylamine structure could be a lead scaffold for novel vitamin D analogs. The structure–activity relationships presented here should be helpful in further development of nonsecosteroidal vitamin D analogs.