First Sila-Vitamin D Analogues: Design, Synthesis, Structural Analysis and Biological Activity
The incorporation of silicon bioisosteres into pharmacological structures has been used as a strategy to improve the therapeutic potential of drugs. However, no secosteroidal silicon-containing VDR ligands have been developed. Here we report the design, synthesis, and biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin D3 (1,25D<sub>3</sub>), which incorporate a silicon atom as a side chain-C25 isostere. The analogues were synthesized by the Wittig-Horner approach starting from Inhoffen-Lythgoe diol. The crystal structures of the complexes formed by the sila-analogues with the ligand binding domain of VDR revealed additional interactions of the sila-containing side chains that stabilize the VDR active conformation. These sila-analogues show similar VDR binding and transcriptional activity in comparison with the natural hormone 1,25D<sub>3</sub>, but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation.
Authors
- Ivo E. Sampaio‐Dias (ORCID: https://orcid.org/0000-0002-9071-6197)
- Julian Loureiro (ORCID: https://orcid.org/0000-0003-4148-1851)
- Carole Peluso‐Iltis
- Antonio Mouriño (ORCID: https://orcid.org/0000-0003-4803-3883)
- Román Pérez-Fernández (ORCID: https://orcid.org/0000-0002-5894-0615)
- Natacha Rochel (ORCID: https://orcid.org/0000-0002-3573-5889)
- Samuel Seoane (ORCID: https://orcid.org/0000-0002-9178-0887)
- Beatriz Brito (ORCID: https://orcid.org/0000-0002-3581-6777)
- Carlos Gregorio
- José E. Rodríguez‐Borges (ORCID: https://orcid.org/0000-0002-9104-1670)
- Thierry Guiberteau
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universidade do Porto (PT)
- Universidade de Santiago de Compostela (ES)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Rede de Química e Tecnologia (PT)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02404
- Citations
- 2
- Primary Topic
- Vitamin D Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Agence Nationale de la Recherche
- European Synchrotron Radiation Facility
- Ministério da Ciência, Tecnologia e Ensino Superior
- Xunta de Galicia
- French Infrastructure for Integrated Structural Biology
- Fundação para a Ciência e a Tecnologia
- Agencia Estatal de Investigación