Design, Synthesis, Evaluation and Structure of Allenic 1α,25‐Dihydroxyvitamin D3 Analogs with Locked Mobility at C‐17
| Autor: | Miguel A. Maestro, Antonio Mouriño, Gilles Laverny, Régis Lutzing, Ramón Fraga, Enrique Rodriguez-Borges, Julian Loureiro, Natacha Rochel, Kateryna Len |
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| Přispěvatelé: | Universidade de Santiago de Compostela [Spain] (USC ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto, Universidade da Coruña, Universidade de Santiago de Compostela. Departamento de Química Orgánica, Universidade do Porto = University of Porto, Rochel, Natacha |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Vitamin D analogs
1α 25 dihydroxyvitamin d3 synthesis [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Stereochemistry Molecular Conformation 010402 general chemistry Ligands 01 natural sciences Calcitriol receptor Catalysis Synthesis Orthoester-Claisen rearrangement Calcitriol Side chain Moiety Allenes Vitamin D Pdcatalyzed reactions Pd-catalyzed reactions [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Full Paper 010405 organic chemistry Chemistry Organic Chemistry Biological activity General Chemistry Full Papers orthoester-Claisen rearrangement 0104 chemical sciences Design synthesis allenes vitamin D analogs Binding domain |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) Chemistry-A European Journal Chemistry-A European Journal, Wiley-VCH Verlag, 2021, 27 (53), pp.13384-13389. ⟨10.1002/chem.202101578⟩ Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname Chemistry-A European Journal, 2021, 27 (53), pp.13384-13389. ⟨10.1002/chem.202101578⟩ |
| ISSN: | 1521-3765 0947-6539 |
| DOI: | 10.1002/chem.202101578⟩ |
| Popis: | Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue‐selective new analogs. We have designed and synthesized the first examples of 1α,25‐dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side‐chain conformational mobility. The triene system was constructed by a Pd0‐mediated cyclization/Suzuki‐Miyaura cross‐coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester‐Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)‐1α,25‐dihydroxy‐17,20‐dien‐24‐homo‐21‐nor‐vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side‐chain conformational requirements for biological activity. Looking for side‐chain conformational requirements of vitamin D analogs for selective biological activity, a new active vitamin D analog that has conformationally restricted mobility at the side chain and adopts a similar structure than the natural hormone 1α,25‐dihydroxyvitamin D3 in the binding pocket was designed by docking and synthesized. The highlights of the synthesis include a Pd0‐catalyzed cascade and an orthoester‐Claisen‐rearrangement for the formation of the trienic system and the allenic side‐chain, respectively. |
| Databáze: | OpenAIRE |
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