Benzoxazines as new human topoisomerase I inhibitors and potential poisons

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dc.contributor.authorFoto, Egemen
dc.contributor.authorOzen, Cigdem
dc.contributor.authorZilifdar, Fatma
dc.contributor.authorTekiner-Gulbas, Betul
dc.contributor.authorYildiz, Ilkay
dc.contributor.authorAki-Yalcin, Esin
dc.contributor.authorDiril, Nuran
dc.date.accessioned2024-02-23T14:00:09Z
dc.date.available2024-02-23T14:00:09Z
dc.date.issued2020
dc.departmentNEÜen_US
dc.description.abstractBackground The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. Objectives In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. Methods We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. Results While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC50:8.34 mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC50:0.0006 mM). BONC-013 was much more poisonous than camptothecin (IC50:0.034 mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R-2 position were play a role for increasing of its poisonous effect. Conclusion As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Graphical abstracten_US
dc.identifier.doi10.1007/s40199-019-00315-x
dc.identifier.endpage73en_US
dc.identifier.issn2008-2231
dc.identifier.issue1en_US
dc.identifier.pmid31832989en_US
dc.identifier.scopus2-s2.0-85076283387en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage65en_US
dc.identifier.urihttps://doi.org/10.1007/s40199-019-00315-x
dc.identifier.urihttps://hdl.handle.net/20.500.12452/11473
dc.identifier.volume28en_US
dc.identifier.wosWOS:000531819500007en_US
dc.identifier.wosqualityQ3en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringer International Publishing Agen_US
dc.relation.ispartofDaru-Journal Of Pharmaceutical Sciencesen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBenzoxazineen_US
dc.subjectAnticanceren_US
dc.subjectTopoisomerase Ien_US
dc.subjectCatalytic Inhibitoren_US
dc.subjectTopoisomerase I Poisonen_US
dc.titleBenzoxazines as new human topoisomerase I inhibitors and potential poisonsen_US
dc.typeArticleen_US

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