2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of New Type of Gemini Analogues with a Cyclopropane Moiety in Their Side Chain

Design, Synthesis, and Biological Evaluation of New Type of Gemini Analogues with a Cyclopropane Moiety in Their Side Chain

  • J Med Chem. 2024 Jun 27;67(12):10386-10400. doi: 10.1021/acs.jmedchem.4c00854.
Uxía Gómez-Bouzó 1,  Carole Peluso-Iltis 2 3 4 5,  Hugo Santalla 1,  Mario Alfredo Quevedo 6,  Lieve Verlinden 7,  Annemieke Verstuyf 7,  Yagamare Fall 1,  Generosa Gómez 1,  Natacha Rochel 2 3 4 5
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica and Instituto de Investigación Sanitaría Galicia Sur (IISGS), Campus Lagoas Marcosende, Universidad de Vigo, Vigo 36310, Spain.
  • 2 Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch 67400, France.
  • 3 CNRS UMR 7104, Illkirch 67400, France.
  • 4 Inserm U1258, Illkirch 67400, France.
  • 5 University of Strasbourg, Illkirch 67400, France.
  • 6 Unidad de Investigación y desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET and Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba X5000HUA, Argentina.
  • 7 Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven 3000, Belgium.
PMID: 38858308 DOI: 10.1021/acs.jmedchem.4c00854
Abstract

We synthesized two new gemini analogues, UG-480 and UG-481, that incorporate a modified longer side chain containing a cyclopropane group. The evaluation of the bioactivities of the two gemini analogues indicated that the 17,20 threo (20S) compound, UG-480, is the most active one and is as active as 1,25(OH)2D3. Docking and molecular dynamics (MD) data showed that the compounds bind efficiently to vitamin D receptor (VDR) with UG-480 to form an energetically more favorable interaction with His397. Structural analysis indicated that whereas the UG-480 compound efficiently stabilizes the active VDR conformation, it induces conformational changes in the H6-H7 VDR region that are greater than those induced by the parental Gemini and that this is due to the occupancy of the secondary channel by its modified side chain.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163947
    Gemini类似物
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