Fujii Shinya, Kano Atsushi, Masuno Hiroyuki, Songkram Chalermkiat, Kawachi Emiko, Hirano Tomoya, Tanatani Aya, Kagechika Hiroyuki
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.
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorg Med Chem Lett. 2014 Sep 15;24(18):4515-4519. doi: 10.1016/j.bmcl.2014.07.075. Epub 2014 Aug 6.
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).
维生素D受体（VDR）是1α,25 - 二羟基维生素D3（1α,25(OH)2D3，1）的核受体，是多种临床应用中很有前景的靶点。我们最近基于含碳硼簇1,12 - 二碳 - 闭式 - 十二硼烷（对 - 碳硼烷）开发了非甾体类VDR配体，并通过晶体学分析研究了其中一种与VDR的结合情况。在此，我们利用该X射线结构设计了新型的基于对 - 碳硼烷的四醇型维生素D类似物，并研究了合成化合物的生物活性。构效关系研究表明，引入ω - 羟基烷氧基官能团可增强生物活性，且取代基的构型对活性有显著影响。在合成的化合物中，4 - 羟基丁氧基衍生物9a表现出最强的活性，其活性与甾体类维生素D类似物19 - 去甲 - 1α,25 - 二羟基维生素D3（2）相当。
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