Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃ (Calcitriol): Refinement of the Side Chain

Zárate-Ruíz, AraceliSeoane Ruzo, SamuelPeluso-Iltis, CarolePeters, StefanGregorio, CarlosGuiberteau, ThierryMaestro, MiguelPérez-Fernández, RománRochel, NatachaMouriño, Antonio2025-01-202025-01-202023-11-01Zárate-Ruíz, A.; Seoane, S.; Peluso-Iltis, C.; Peters, S.; Gregorio, C.; Guiberteau, T.; Maestro, M.; Pérez-Fernández, R.; Rochel, N.; Mouriño, A. Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃ (Calcitriol): Refinement of the Side Chain. J. Med. Chem. 2023, 66 (22), 15326–15339. https://doi.org/10.1021/acs.jmedchem.3c013711520-4804http://hdl.handle.net/2183/40786This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2023 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.3c01371.[Abstract] Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1α,25-dihydroxyvitamin D₃ (1,25D₃). We have recently reported the design, synthesis, biological evaluation, and crystal structures of a series of novel analogues that both lack the steroidal C-ring and have an m-phenylene ring replacing the steroidal cyclopentane D-ring. We have now investigated the potentiating effects of incorporating selected modifications (hexafluorination and/or an internal triple bond) within the steroidal side chain in our series. An alternative synthetic strategy (Wittig–Horner approach instead of our previously used Pd-catalyzed tandem cyclization/cross-coupling) for the construction of the vitamin D triene system was found convenient for the target compounds 2, 3a, 3b, and 3c of this report. These modifications enhance vitamin D nuclear receptor (VDR) interactions and consequently VDR-associated biological properties compared to parental PG-136 compound while maintaining normal calcium levels.engNoncalcemic des-C-ring vitamin D analogsAromatic D-ring analogsCalcemiaAntiproliferationDesignSynthesisCrystal structureFurther Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃ (Calcitriol): Refinement of the Side Chainjournal articleopen access10.1021/acs.jmedchem.3c01371