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
  • 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.

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