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

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

doi:10.1016/j.bmcl.2014.07.075

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

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4515-4519. doi: 10.1016/j.bmcl.2014.07.075. Epub 2014 Aug 6.

Authors

Shinya Fujii¹, 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: 25149512
DOI: 10.1016/j.bmcl.2014.07.075

Abstract

Vitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 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 D3 (2).

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

Publication types

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

MeSH terms

Boron Compounds / chemical synthesis*
Boron Compounds / chemistry
Boron Compounds / pharmacology*
Crystallography, X-Ray
Drug Design*
Humans
Ligands
Models, Molecular
Molecular Structure
Receptors, Calcitriol / metabolism*
Vitamin D / analogs & derivatives*
Vitamin D / chemistry

Substances

1,12-dicarba-closo-dodecaborane
Boron Compounds
Ligands
Receptors, Calcitriol
Vitamin D