Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes
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 <i>N</i>-alkyl-acridones <b>1</b>−...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/9/5/177 |
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| author | Marios G. Krokidis Zara Molphy Eleni K. Efthimiadou Marianna Kokoli Smaragda-Maria Argyri Irini Dousi Annalisa Masi Kyriakos Papadopoulos Andrew Kellett Chryssostomos Chatgilialoglu |
| author_facet | Marios G. Krokidis Zara Molphy Eleni K. Efthimiadou Marianna Kokoli Smaragda-Maria Argyri Irini Dousi Annalisa Masi Kyriakos Papadopoulos Andrew Kellett Chryssostomos Chatgilialoglu |
| author_sort | Marios G. Krokidis |
| collection | DOAJ |
| description | 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 <i>N</i>-alkyl-acridones <b>1</b>−<b>6</b> and <i>N</i>,<i>N</i>′-dialkyl-9,9′-biacridylidenes <b>7</b>−<b>12</b> 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. <i>N</i>-alkyl-acridone derivatives <b>1</b>−<b>6</b> exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes <b>7</b>−<b>12</b>, 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 <i>N</i>,<i>N′</i>-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. |
| first_indexed | 2024-12-23T11:17:11Z |
| format | Article |
| id | doaj.art-5e404e14169d4ee681544ee886fff647 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-12-23T11:17:11Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
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| series | Biomolecules |
| spelling | doaj.art-5e404e14169d4ee681544ee886fff6472022-12-21T17:49:11ZengMDPI AGBiomolecules2218-273X2019-05-019517710.3390/biom9050177biom9050177Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenesMarios G. Krokidis0Zara Molphy1Eleni K. Efthimiadou2Marianna Kokoli3Smaragda-Maria Argyri4Irini Dousi5Annalisa Masi6Kyriakos Papadopoulos7Andrew Kellett8Chryssostomos Chatgilialoglu9Institute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceSchool of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, IrelandInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceISOF, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, ItalyInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceSchool of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, IrelandInstitute of Nanoscience and Nanotechnology, N.C.S.R. “Demokritos”, 15310 Agia Paraskevi-Athens, GreeceThe 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 <i>N</i>-alkyl-acridones <b>1</b>−<b>6</b> and <i>N</i>,<i>N</i>′-dialkyl-9,9′-biacridylidenes <b>7</b>−<b>12</b> 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. <i>N</i>-alkyl-acridone derivatives <b>1</b>−<b>6</b> exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes <b>7</b>−<b>12</b>, 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 <i>N</i>,<i>N′</i>-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.https://www.mdpi.com/2218-273X/9/5/177<i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenestopoisomerase IDNA intercalationDNA bindingradical scavenging capacitycytotoxic activity |
| spellingShingle | Marios G. Krokidis Zara Molphy Eleni K. Efthimiadou Marianna Kokoli Smaragda-Maria Argyri Irini Dousi Annalisa Masi Kyriakos Papadopoulos Andrew Kellett Chryssostomos Chatgilialoglu Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes Biomolecules <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes topoisomerase I DNA intercalation DNA binding radical scavenging capacity cytotoxic activity |
| title | Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes |
| title_full | Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes |
| title_fullStr | Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes |
| title_full_unstemmed | Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes |
| title_short | Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of <i>N</i>-alkyl-acridones and <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes |
| title_sort | assessment of dna topoisomerase i unwinding activity radical scavenging capacity and inhibition of breast cancer cell viability of i n i alkyl acridones and i n i i n i dialkyl 9 9 biacridylidenes |
| topic | <i>N</i>,<i>N′</i>-dialkyl-9,9′-biacridylidenes topoisomerase I DNA intercalation DNA binding radical scavenging capacity cytotoxic activity |
| url | https://www.mdpi.com/2218-273X/9/5/177 |
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