2. Academic Validation
  3. Synthesis of novel imino-coumarin and acrylonitrile 2-benzazole hybrids as potent anticancer agents targeting tubulin

Synthesis of novel imino-coumarin and acrylonitrile 2-benzazole hybrids as potent anticancer agents targeting tubulin

  • Bioorg Chem. 2024 Nov 22:154:107991. doi: 10.1016/j.bioorg.2024.107991.
Ida Boček Pavlinac 1,  Leentje Persoons 2,  Anja Beč 1,  Lucija Vrban 3,  Dirk Daelemans 2,  Robert Vianello 4,  Marijana Hranjec 5
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
  • 2 KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven, Belgium.
  • 3 Laboratory for the computational design and synthesis of functional materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia.
  • 4 Laboratory for the computational design and synthesis of functional materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia. Electronic address: robert.vianello@irb.hr.
  • 5 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia. Electronic address: mhranjec@fkit.unizg.hr.
PMID: 39612743 DOI: 10.1016/j.bioorg.2024.107991
Abstract

Building on previous research indicating the robust biological effects of Coumarins, we focused on exploring imino-coumarin 2-benzazole conjugates. Compounds were tested for antiproliferative activity in vitro, with the most active ones further examined to determine the mechanism of biological action. Five derivatives exhibited significant antiproliferative activity against all tested Cancer cells (IC50 ranging from 0.04 to 8.5 μM), falling within the low micromolar/submicromolar range of inhibitory concentrations. Three compounds had remarkable antiproliferative effects against Capan-1 (IC50 0.04-0.05 μM) and DND-41 (IC50 0.06-0.07 μM). Promising compounds were further investigated, confirming their mechanism of action through tubulin polymerization inhibition. Computational docking and molecular dynamics simulations confirmed the high affinity of potent derivatives for the tubulin colchicine site and justified the suitability of the employed skeleton by identifying crucial protein-ligand interactions promoting binding. This insight highlights a strategy for further potency improvements through substituents that can donate hydrogen bonds or bear a positive charge, allowing such ligands to more optimally adapt to the identified anionic binding site environment.

Keywords

Antiproliferative activity; Benzazoles; Computational chemistry; Drug design; Imino-coumarins; Tubulin polymerization inhibitors.

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