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.

Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D₃ (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted S_N2′-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson–Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.