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

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Abstract
Current efforts in the vitamin D field are directed toward the development of highly antiproliferative yet noncalcemic analogues of the natural hormone 1 alpha,25-dihydroxyvitamin D-3 (1,25D(3)). 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.
Funding Information
  • Agence Nationale de la Recherche (ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02, ANR-21-CE17-0009-01)
  • Universit? de Strasbourg
  • Institut National de la Sant? et de la Recherche M?dicale
  • Deutscher Akademischer Austauschdienst
  • Ministerio de Ciencia e Innovaci?n (MICIN/AEI/PGC2018-100776-B-I00, MICIN/AEI/PID2021-127394OB-100)
  • Xunta de Galicia (GRC/ED431B/2021/004)
  • Centre National de la Recherche Scientifique
  • Institut de g?n?tique et de biologie mol?culaire et cellulaire

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