Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D 3

• Published in: Journal of medicinal chemistry Vol. 65; no. 19; pp. 13112 - 13124
• Main Authors: Seoane, Samuel, Gogoi, Pranjal, Zárate-Ruíz, Araceli, Peluso-Iltis, Carole, Peters, Stefan, Guiberteau, Thierry, Maestro, Miguel A., Pérez-Fernández, Román, Rochel, Natacha, Mouriño, Antonio
• Format: Journal Article
• Language: English
• Published: American Chemical Society 13.10.2022
• Subjects: Life Sciences
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00900

The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 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 1,25D3 that lack the C-ring and possess an mphenylene 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 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.