期刊
CHEMICAL SCIENCE
卷 7, 期 2, 页码 1033-1037出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc03084f
关键词
-
资金
- Spanish Ministry of Economy and Innovation (MEI) [SAF2010-15291, SAF2012-38240]
- Xunta de Galicia [GPC2014/001, POS-A/2012/112]
- Agence Nationale de la Recherche [ANR-13-BSV8-0024-01]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01]
- INSTRUCT as part of the European Strategy Forum on Research Infrastructures (ESFRI)
- Spanish MEI [BES-2011-0419192]
- Asociacion Espanola Contra el Cancer [AIOA1101SEOA]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV8-0024] Funding Source: Agence Nationale de la Recherche (ANR)
The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1 alpha, 25-dihydroxyvitamin D-3 (1,25D) and an o-carborane (dicarba-o-closo-1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and development.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据