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Chem Sci. 2016 Feb 1;7(2):1033-1037. doi: 10.1039/c5sc03084f. Epub 2015 Oct 27.

Carborane-based design of a potent vitamin D receptor agonist.

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Departamento de Química Orgánica , Laboratorio de Investigación Ignacio Ribas , Universidad de Santiago de Compostela , Avda. Ciencias s/n , 15782 Santiago de Compostela , Spain . Email:
Departamento de Fisiología-CIMUS , Universidad de Santiago , Avda. Barcelona s/n , 15706 Santiago de Compostela , Spain.
Department of Integrative Structural Biology , IGBMC - CNRS UMR7104 - Inserm U964 , 1, rue Laurent Fries , 67400 Illkirch , France . Email:
Departmento de Química Fundamental , Universidad de A Coruña , Campus da Zapateira s/n , 15071 A Coruña , Spain.


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 1α,25-dihydroxyvitamin D3 (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.

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