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Publication Abstract from PubMed

The 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.