Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells
New 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 fol...
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MDPI AG
2021-04-01
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| author | Anna Mieszkowska Anna M. Nowicka Agata Kowalczyk Agnieszka Potęga Monika Pawłowska Michał Kosno Ewa Augustin Zofia Mazerska |
| author_facet | Anna Mieszkowska Anna M. Nowicka Agata Kowalczyk Agnieszka Potęga Monika Pawłowska Michał Kosno Ewa Augustin Zofia Mazerska |
| author_sort | Anna Mieszkowska |
| collection | DOAJ |
| description | New 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. |
| first_indexed | 2024-03-10T12:42:22Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T12:42:22Z |
| publishDate | 2021-04-01 |
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| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-33875ddea39b432b90bf1e1d31950aa12023-11-21T13:47:13ZengMDPI AGPharmaceuticals1424-82472021-04-0114431710.3390/ph14040317Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor CellsAnna Mieszkowska0Anna M. Nowicka1Agata Kowalczyk2Agnieszka Potęga3Monika Pawłowska4Michał Kosno5Ewa Augustin6Zofia Mazerska7Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandFaculty of Chemistry, University of Warsaw, Pasteura Str. 1, 02-093 Warsaw, PolandFaculty of Chemistry, University of Warsaw, Pasteura Str. 1, 02-093 Warsaw, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza Str. 11/12, 80-233 Gdańsk, PolandNew 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.https://www.mdpi.com/1424-8247/14/4/317antitumor unsymmetrical bisacridinesdrugs in cell medium/extractdrugs under electrochemical transformationsFMO catalyzed metabolismP450-mediated drug metabolismUGT metabolic transformations |
| spellingShingle | Anna Mieszkowska Anna M. Nowicka Agata Kowalczyk Agnieszka Potęga Monika Pawłowska Michał Kosno Ewa Augustin Zofia Mazerska Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells Pharmaceuticals antitumor unsymmetrical bisacridines drugs in cell medium/extract drugs under electrochemical transformations FMO catalyzed metabolism P450-mediated drug metabolism UGT metabolic transformations |
| title | Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells |
| title_full | Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells |
| title_fullStr | Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells |
| title_full_unstemmed | Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells |
| title_short | Metabolic Profiles of New Unsymmetrical Bisacridine Antitumor Agents in Electrochemical and Enzymatic Noncellular Systems and in Tumor Cells |
| title_sort | metabolic profiles of new unsymmetrical bisacridine antitumor agents in electrochemical and enzymatic noncellular systems and in tumor cells |
| topic | antitumor unsymmetrical bisacridines drugs in cell medium/extract drugs under electrochemical transformations FMO catalyzed metabolism P450-mediated drug metabolism UGT metabolic transformations |
| url | https://www.mdpi.com/1424-8247/14/4/317 |
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