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Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3.
Seoane, Samuel; Gogoi, Pranjal; Zárate-Ruíz, Araceli; Peluso-Iltis, Carole; Peters, Stefan; Guiberteau, Thierry; Maestro, Miguel A; Pérez-Fernández, Román; Rochel, Natacha; Mouriño, Antonio.
Afiliação
  • Seoane S; Department of Physiology-Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Avda. Barcelona s/n, Santiago de Compostela 15706, Spain.
  • Gogoi P; Department of Organic Chemistry, Research Laboratory Ignacio Ribas, University of Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela 15782, Spain.
  • Zárate-Ruíz A; Department of Organic Chemistry, Research Laboratory Ignacio Ribas, University of Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela 15782, Spain.
  • Peluso-Iltis C; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Institut National de La Santé et de La Recherche Médicale (INSERM), U1258; Centre National de Recherche Scientifique (CNRS), UMR7104, Université de Strasbourg, Strasbourg, Illkirch 67400, France.
  • Peters S; Department of Organic Chemistry, Research Laboratory Ignacio Ribas, University of Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela 15782, Spain.
  • Guiberteau T; Laboratoire ICube─Université de Strasbourg, CNRS UMR 7357, Strasbourg 67000, France.
  • Maestro MA; Department of Chemistry-CICA, University of A Coruña, Campus da Zapateira s/n, A Coruña 15071, Spain.
  • Pérez-Fernández R; Department of Physiology-Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Avda. Barcelona s/n, Santiago de Compostela 15706, Spain.
  • Rochel N; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Institut National de La Santé et de La Recherche Médicale (INSERM), U1258; Centre National de Recherche Scientifique (CNRS), UMR7104, Université de Strasbourg, Strasbourg, Illkirch 67400, France.
  • Mouriño A; Department of Organic Chemistry, Research Laboratory Ignacio Ribas, University of Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela 15782, Spain.
J Med Chem ; 65(19): 13112-13124, 2022 10 13.
Article em En | MEDLINE | ID: mdl-36166643
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Calcitriol / Receptores de Calcitriol Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Calcitriol / Receptores de Calcitriol Idioma: En Ano de publicação: 2022 Tipo de documento: Article