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Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells

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dc.abstract.enNew unsymmetrical bisacridines (UAs) demonstrated high activity not only against a set of tumor cell lines but also against human tumor xenografts in nude mice. Representative UA compounds, named C-2028, C-2045 and C-2053, were characterized in respect to their physicochemical properties and the following studies aimed to elucidate the role of metabolic transformations in UAs action. We demonstrated with phase I and phase II enzymes in vitro and in tumors cells that: (i) metabolic products generated by cytochrome P450 (P450), flavin monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) isoenzymes in noncellular systems retained the compound’s dimeric structures, (ii) the main transformation pathway is the nitro group reduction with P450 isoenzymes and the metabolism to N-oxide derivative with FMO1, (iii), the selected UGT1 isoenzymes participated in the glucuronidation of one compound, C-2045, the hydroxy derivative. Metabolism in tumor cells, HCT-116 and HT-29, of normal and higher UGT1A10 expression, respectively, also resulted in the glucuronidation of only C-2045 and the specific distribution of all compounds between the cell medium and cell extract was demonstrated. Moreover, P4503A4 activity was inhibited by C-2045 and C-2053, whereas C-2028 affected UGT1A and UGT2B action. The above conclusions indicate the optimal strategy for the balance among antitumor therapeutic efficacy and drug resistance in the future antitumor therapy.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMieszkowska, Anna
dc.contributor.authorPotęga, Agnieszka
dc.contributor.authorNowicka, Anna
dc.contributor.authorKowalczyk, Agata
dc.contributor.authorAugustin, Ewa
dc.contributor.authorMazerska, Zofia
dc.contributor.authorPawłowska, Monika
dc.contributor.authorKosno, Michał
dc.date.accessioned2024-01-25T11:27:37Z
dc.date.available2024-01-25T11:27:37Z
dc.date.copyright2021-04-01
dc.date.issued2021
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number4
dc.description.versionFINAL_PUBLISHED
dc.description.volume14
dc.identifier.doi10.3390/PH14040317
dc.identifier.issn1424-8247
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112310
dc.identifier.weblinkhttps://www.mdpi.com/1424-8247/14/4/317/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofPharmaceuticals
dc.relation.pagesart.no. 317
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enAntitumor unsymmetrical bisacridines
dc.subject.enDrugs in cell medium/extract
dc.subject.enDrugs under electrochemical transformations
dc.subject.enFMO catalyzed metabolism
dc.subject.enP450-mediated drug metabolism
dc.subject.enUGT metabolic transformations
dc.titleMetabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells
dc.typeJournalArticle
dspace.entity.typePublication