8PWE

Crystal structure of VDR complex with Novel Des-C-Ring and Aromatic-D-Ring analog 3a

Summary for 8PWE

• Entry DOI: 10.2210/pdb8pwe/pdb
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 2, ACETATE ION, ... (5 entities in total)
• Functional Keywords: nuclear receptor, vdr, agonist, transcription
• Biological source: Danio rerio (zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 36094.13

Authors

Rochel, N. (deposition date: 2023-07-20, release date: 2024-08-07, Last modification date: 2025-03-12)

Primary citation

Zarate-Ruiz, A.,Seoane, S.,Peluso-Iltis, C.,Peters, S.,Gregorio, C.,Guiberteau, T.,Maestro, M.,Perez-Fernandez, R.,Rochel, N.,Mourino, A.
Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1 alpha ,25-Dihydroxyvitamin D 3 (Calcitriol): Refinement of the Side Chain.
J.Med.Chem., 66:15326-15339, 2023

PubMed 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 D (1,25D). 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 -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 , , , and 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.

PubMed: 37910811
DOI: 10.1021/acs.jmedchem.3c01371

Experimental method

X-RAY DIFFRACTION (2 Å)