2. Academic Validation
  3. Thalidomide derivatives as nanomolar human neutrophil elastase inhibitors: Rational design, synthesis, antiproliferative activity and mechanism of action

Thalidomide derivatives as nanomolar human neutrophil elastase inhibitors: Rational design, synthesis, antiproliferative activity and mechanism of action

  • Bioorg Chem. 2023 Sep;138:106608. doi: 10.1016/j.bioorg.2023.106608.
Beata Donarska 1,  Adrianna Sławińska-Brych 2,  Magdalena Mizerska-Kowalska 3,  Barbara Zdzisińska 3,  Wojciech Płaziński 4,  Krzysztof Z Łączkowski 5
Affiliations

Affiliations

  • 1 Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland. Electronic address: [email protected].
  • 2 Department of Cell Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19 Street, 20-033 Lublin, Poland.
  • 3 Department of Virology and Immunology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19 Street, 20-033 Lublin, Poland.
  • 4 Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239, Cracow, Poland; Department of Biopharmacy, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland.
  • 5 Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland.
PMID: 37207596 DOI: 10.1016/j.bioorg.2023.106608
Abstract

Here, we rationally designed a human neutrophil Elastase (HNE) inhibitors 4a-4f derived from thalidomide. The HNE inhibition assay showed that synthesized compounds 4a, 4b, 4e and 4f demonstrated strong HNE inhibiton properties with IC50 values of 21.78-42.30 nM. Compounds 4a, 4c, 4d and 4f showed a competitive mode of action. The most potent compound 4f shows almost the same HNE inhibition as sivelestat. The molecular docking analysis revealed that the strongest interactions occur between the azetidine-2,4-dione group and the following three aminoacids: Ser195, Arg217 and His57. A high correlation between the binding energies and the experimentally determined IC50 values was also demonstrated. The study of antiproliferative activity against human T47D (breast carcinoma), RPMI 8226 (multiple myeloma), and A549 (non-small-cell lung carcinoma) revealed that designed compounds were more active compared to thalidomide, pomalidomide and lenalidomide used as the standard drugs. Additionally, the most active compound 4f derived from lenalidomide induces cell cycle arrest at the G2/M phase and Apoptosis in T47D cells.

Keywords

Antiproliferative activity; Competitive inhibitor; Human neutrophil elastase; Molecular docking; Thalidomide.

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