2. Academic Validation
  3. Development of 2,9-Disubstituted Acridines as Topoisomerase IIα Inhibitors with Strong Anticancer Activity: Synthesis, Biological Evaluation, and In Silico Study

Development of 2,9-Disubstituted Acridines as Topoisomerase IIα Inhibitors with Strong Anticancer Activity: Synthesis, Biological Evaluation, and In Silico Study

  • ChemMedChem. 2025 May 25:e2500267. doi: 10.1002/cmdc.202500267.
Ladislav Janovec 1,  Adrian Gucký 2,  Kristína Krochtová 2,  Radka Michalková 3,  Katarína Kušnírová 1,  Viktória Miškufová 3,  Dávid Jáger 4,  Ján Mojžiš 3,  Mária Kožurková 2
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01, Košice, Slovak Republic.
  • 2 Department of Biochemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University in Košice, Moyzesova 11, 040 01, Košice, Slovak Republic.
  • 3 Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University in Kosice, Tr. SNP 1, 040 11, Košice, Slovak Republic.
  • 4 Institute of Geotechnics, Slovak Academy of Sciences, Watsonova 45, 040 01, Kosice, Slovak Republic.
PMID: 40415460 DOI: 10.1002/cmdc.202500267
Abstract

A series of 2,9-disubstituted acridines (16a-16h) is synthetized and assessed for their biological activities. The acridines feature various 9-anilino or 9-phenylalkyl substituents and are prepared via a linear sequence of six steps using commercially available starting Materials. The relationship between the physicochemical properties of the 2,9-disubstituted acridines and their biological activity is studied, and the DNA binding capacities of the synthetized acridines are determined using spectroscopic (Kb 0.5-10.4 × 104 M-1) and thermal denaturation (ΔTm 4.2-9.8 °C) methods. The inhibitory potential of acridines 16a-16h toward human Topoisomerase I/IIα is evaluated, and 9-phenylbutyl acridine 16h is found to inhibit human Topoisomerase IIα at concentrations as low as 5 μm. Acridines 16a-16h are also subjected to in vitro screening against selected Cancer cell lines; the most potent Anticancer activity is observed against melanoma A2058 cell lines at IC50 values ranging from 3 to 6 μm.

Keywords

DNA binding; acridines; cytotoxic activity; molecular modeling; topoisomerase inhibition.

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