Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines

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dc.contributor.authorKruschel, Ryan D.
dc.contributor.authorBuzid, Alyah
dc.contributor.authorKhandavilli, Udaya Bhaskara Rao
dc.contributor.authorLawrence, Simon E.
dc.contributor.authorGlennon, Jeremy D.
dc.contributor.authorMcCarthy, Florence O.
dc.contributor.funderIrish Research Councilen
dc.contributor.funderEuropean Cooperation in Science and Technologyen
dc.date.accessioned2020-02-11T15:22:51Z
dc.date.available2020-02-11T15:22:51Z
dc.date.issued2019-12-18
dc.date.updated2020-02-11T15:11:18Z
dc.description.abstractThe isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationKruschel, R. D., Buzid, A., Khandavilli, U. B. R., Lawrence, S. E., Glennon, J. D. and McCarthy, F. O. (2020) 'Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines', Organic & Biomolecular Chemistry, 18(3), pp. 557-568. doi: 10.1039/C9OB02441Gen
dc.identifier.doi10.1039/C9OB02441Gen
dc.identifier.endpage568en
dc.identifier.issn1477-0520
dc.identifier.issued3en
dc.identifier.journaltitleOrganic & Biomolecular Chemistryen
dc.identifier.startpage557en
dc.identifier.urihttps://hdl.handle.net/10468/9633
dc.identifier.volume18en
dc.language.isoenen
dc.publisherRoyal Society of Chemistryen
dc.relation.projectEuropean Cooperation in Science and Technology (COST Action CA15135)en
dc.relation.urihttps://pubs.rsc.org/en/content/articlehtml/2020/ob/c9ob02441g
dc.rightshttps://pubs.rsc.org/en/content/articlelanding/2020/OB/C9OB02441Gen
dc.subjectLead compoundsen
dc.subjectAmino acidsen
dc.subjectCell cultureen
dc.subjectCellsen
dc.subjectTumorsen
dc.subjectAnti-cancer agentsen
dc.subjectAnticancer potentialsen
dc.subjectCancer cell linesen
dc.subjectElectrochemical studiesen
dc.subjectGrowth inhibitionen
dc.subjectNatural productsen
dc.subjectPharmacophoresen
dc.subjectResistant cellsen
dc.titleIsoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell linesen
dc.typeArticle (peer-reviewed)en
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