期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 51, 页码 20933-20941出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja208797n
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [21790110, 22790106, 19201044, 19689004]
- Takeda Science Foundation
- Mitsubishi Foundation
- Grants-in-Aid for Scientific Research [20390035, 22790106, 21790110, 23659051, 19201044, 23790128, 22136013, 19689004] Funding Source: KAKEN
We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.
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