Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs

Shinya Fujii; Ryota Sekine; Atsushi Kano; Hiroyuki Masuno; Chalermkiat Songkram; Emiko Kawachi; Tomoya Hirano; Aya Tanatani; Hiroyuki Kagechika

doi:10.1016/j.bmc.2014.09.020

Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs

Bioorg Med Chem. 2014 Nov 1;22(21):5891-901. doi: 10.1016/j.bmc.2014.09.020. Epub 2014 Sep 16.

Authors

Shinya Fujii¹, Ryota Sekine², Atsushi Kano², Hiroyuki Masuno², Chalermkiat Songkram³, Emiko Kawachi², Tomoya Hirano², Aya Tanatani⁴, Hiroyuki Kagechika⁵

Affiliations

¹ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
² Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Kho-Hong, Hat Yai, Songkhla 90112, Thailand.
⁴ Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
⁵ Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: kage.chem@tmd.ac.jp.

PMID: 25284253
DOI: 10.1016/j.bmc.2014.09.020

Abstract

Non-secosteroidal vitamin D receptor (VDR) ligands are promising candidates for many clinical applications. We recently developed novel non-secosteroidal VDR agonists based on p-carborane (an icosahedral carbon-containing boron cluster) as a hydrophobic core structure. Here, we report the design, synthesis and biological evaluation of carborane-based vitamin D analogs bearing various substituents at the diol moiety. Among the synthesized compounds, methylene derivative 31 exhibited the most potent vitamin D activity, which was comparable to that of the natural hormone, 1α,25(OH)2D3. This compound is one of the most potent non-secosteroidal VDR agonists reported to date, and is a promising lead for development of novel drug candidates.

Keywords: Carborane; Non-secosteroid; Nuclear receptor; Vitamin D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Boranes / chemical synthesis
Boranes / chemistry*
Boranes / pharmacology
Cell Differentiation / drug effects
Drug Design
HL-60 Cells
Humans
Ligands
Protein Binding
Receptors, Calcitriol / agonists
Receptors, Calcitriol / metabolism
Structure-Activity Relationship
Vitamin D / analogs & derivatives*
Vitamin D / chemical synthesis
Vitamin D / pharmacology

Substances

Boranes
Ligands
Receptors, Calcitriol
Vitamin D