Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs.
Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs.
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DOI：
10.1016/j.bmcl.2014.07.075
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发表时间：
2014-09
影响因子：
2.7
通讯作者：
S. Fujii;Atsushi Kano;H. Masuno;C. Songkram;E. Kawachi;T. Hirano;Aya Tanatani;H. Kagechika
中科院分区：
文献类型：
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作者：
S. Fujii;Atsushi Kano;H. Masuno;C. Songkram;E. Kawachi;T. Hirano;Aya Tanatani;H. Kagechika
维生素D受体（VDR）是1α，25-二羟维生素D3（1α，25（OH）2D 3，1）的核受体，是一个具有广泛临床应用前景的靶点。我们最近开发了非开环甾类VDR配体的基础上的含碳硼簇，1，12-二碳-closo-dodecorane（p-碳硼烷），并研究了其中之一的结合VDR通过晶体学分析。在这里，我们利用这种X射线结构来设计新的基于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，ω-羟基烷氧基官能团的引入提高了化合物的生物活性，取代基的构型对活性有显著影响。在所合成的化合物中，4-羟基丁氧基衍生物9a表现出最强的活性，与开环甾体维生素D类似物19-去甲-1 α，25-二羟基维生素D3（2）的活性相当。
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 novelp-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 derivative9aexhibited the most potent activity, which was equal to that of the secosteroidal vitamin D analog, 19-nor-1α,25-dihydroxyvitamin D3(2).