Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃

Seoane Ruzo, SamuelGogoi, PranjalZárate-Ruíz, AraceliPeluso-Iltis, CarolePeters, StefanGuiberteau, ThierryMaestro, MiguelPérez-Fernández, RománRochel, NatachaMouriño, Antonio2025-01-202025-01-202022-09-27Seoane, S.; Gogoi, P.; Zárate-Ruíz, A.; Peluso-Iltis, C.; Peters, S.; Guiberteau, T.; Maestro, M. A.; Pérez-Fernández, R.; Rochel, N.; Mouriño, A. Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃. J. Med. Chem. 2022, 65 (19), 13112–13124. https://doi.org/10.1021/acs.jmedchem.2c009001520-4804http://hdl.handle.net/2183/40785This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c00900.[Abstract] 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 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 1,25D₃. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.engAromatic compoundsLigandsMixturesNutritionOrganic compoundsDesign, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D₃journal articleopen access10.1021/acs.jmedchem.2c00900