7zfg
VDR complex with aromatic D-ring analog
Structural highlights
FunctionVDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMedThe toxic calcemic effects of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (1,25D(3), 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D(3) that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D(3). Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6. Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1alpha,25-Dihydroxyvitamin D(3).,Seoane S, Gogoi P, Zarate-Ruiz A, Peluso-Iltis C, Peters S, Guiberteau T, Maestro MA, Perez-Fernandez R, Rochel N, Mourino A J Med Chem. 2022 Oct 13;65(19):13112-13124. doi: 10.1021/acs.jmedchem.2c00900. , Epub 2022 Sep 27. PMID:36166643[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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