Synthesis, computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors

Abdel-Hafez, Gehan A., Mohamed, Abdel-Maaboud I., Youssef, Adel F., Simons, Claire ORCID: https://orcid.org/0000-0002-9487-1100 and Aboraia, Ahmed S. 2022. Synthesis, computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry 37 (1) , pp. 502-513. 10.1080/14756366.2021.2021898

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Abstract

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8–17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8–10) revealed 60–97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC50 0.52 µM) compared with doxorubicin (IC50 0.83 µM). Molecular dynamics simulation studies showed the acridine–triazole–pyrimidine hybrid pharmacophore was optimal with respect to protein–ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Pharmacy
Additional Information:	This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/)
Publisher:	Taylor & Francis Open Access
ISSN:	1475-6366
Date of First Compliant Deposit:	26 January 2022
Date of Acceptance:	16 December 2021
Last Modified:	12 Jul 2024 16:03
URI:	https://orca.cardiff.ac.uk/id/eprint/146990

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