Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain - Ecole Nationale du Génie de l'Eau et de l'Environnement de Strasbourg
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2023

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

Résumé

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.
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Dates et versions

hal-04299017 , version 1 (04-09-2024)

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Araceli Zárate-Ruíz, Samuel Seoane, Carole Peluso-Iltis, Stefan Peters, Carlos Gregorio, et al.. Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain. Journal of Medicinal Chemistry, 2023, 66 (22), pp.15326-15339. ⟨10.1021/acs.jmedchem.3c01371⟩. ⟨hal-04299017⟩
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