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Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of N-alkyl-acridones and N,N′-dialkyl-9,9′-biacridylidenes

1
Institute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, Greece
2
School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland
3
Department of Chemistry, National and Kapodistrian University of Athens, 15784 Zografou, Greece
4
ISOF, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy
*
Authors to whom correspondence should be addressed.
Present address: Department of Chemistry and Chemical Engineering, Chemistry and Biochemistry, Chalmers University of Technology, SE-41296, Gothenburg, Sweden.
Biomolecules 2019, 9(5), 177; https://doi.org/10.3390/biom9050177
Received: 20 April 2019 / Revised: 6 May 2019 / Accepted: 7 May 2019 / Published: 8 May 2019
(This article belongs to the Special Issue 2019 Feature Papers by Biomolecules’ Editorial Board Members)
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Abstract

The anticancer activity of acridone derivatives has attracted increasing interest, therefore, a variety of substituted analogs belonging to this family have been developed and evaluated for their anti-cancer properties. A series of N-alkyl-acridones 16 and N,N′-dialkyl-9,9′-biacridylidenes 712 with variable alkyl chains were examined for their topoisomerase I activity at neutral and acidic conditions as well as for their binding capacity to calf thymus and possible radical trapping antioxidant activity. It was found that at a neutral pH, topoisomerase I activity of both classes of compounds was similar, while under acidic conditions, enhanced intercalation was observed. N-alkyl-acridone derivatives 16 exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than N,N′-dialkyl-9,9′-biacridylidenes 712, revealing that conjugation of the heteroaromatic system plays a significant role on the effective distribution of the compound in the intracellular environment. Cellular investigation of long alkyl derivatives against cell migration exhibited 40–50% wound healing effects and cytoplasm diffusion, while compounds with shorter alkyl chains were accumulated both in the nucleus and cytoplasm. All N,N′-dialkyl-9,9′-biacridylidenes showed unexpected high scavenging activity towards DPPH or ABTS radicals which may be explained by higher stabilization of radical cations by the extended conjugation of heteroaromatic ring system. View Full-Text
Keywords: N,N′-dialkyl-9,9′-biacridylidenes; topoisomerase I; DNA intercalation; DNA binding; radical scavenging capacity; cytotoxic activity N,N′-dialkyl-9,9′-biacridylidenes; topoisomerase I; DNA intercalation; DNA binding; radical scavenging capacity; cytotoxic activity
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Krokidis, M.G.; Molphy, Z.; Efthimiadou, E.K.; Kokoli, M.; Argyri, S.-M.; Dousi, I.; Masi, A.; Papadopoulos, K.; Kellett, A.; Chatgilialoglu, C. Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of N-alkyl-acridones and N,N′-dialkyl-9,9′-biacridylidenes. Biomolecules 2019, 9, 177.

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