Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties
AbstractMolecular docking of a large set of thiosemicarbazide-based ligands resulted in obtaining compounds that inhibited both human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase-1 (IDO1). To the best of our knowledge, these compounds are the first dual inhibitors targeting these two enzyme...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2140420 |
| _version_ | 1797400956747382784 |
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| author | Barbara Kaproń Anita Płazińska Wojciech Płaziński Tomasz Plech |
| author_facet | Barbara Kaproń Anita Płazińska Wojciech Płaziński Tomasz Plech |
| author_sort | Barbara Kaproń |
| collection | DOAJ |
| description | AbstractMolecular docking of a large set of thiosemicarbazide-based ligands resulted in obtaining compounds that inhibited both human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase-1 (IDO1). To the best of our knowledge, these compounds are the first dual inhibitors targeting these two enzymes. As both of them participate in the anticancer response, the effect of the compounds on a panel of cancer cell lines was examined. Among the cell lines tested, lung cancer (A549) and melanoma (A375) cells were the most sensitive to compounds 1 (IC50=0.23 µg/ml), 2 (IC50=0.83 µg/ml) and 3 (IC50=0.25 µg/ml). The observed activity was even 90-fold higher than that of etoposide, with selectivity index values reaching 125. In-silico simulations showed that contact between 1-3 and human DNA topoisomerase II was maintained through aromatic moieties located at limiting edges of ligand molecules and intensive interactions of the thiosemicarbazide core with the DNA fragments present in the catalytic site of the enzyme. |
| first_indexed | 2024-03-09T02:03:00Z |
| format | Article |
| id | doaj.art-95c6df3aff69450fa3d3979b9a14a22f |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-03-09T02:03:00Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-95c6df3aff69450fa3d3979b9a14a22f2023-12-08T03:24:22ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138119220210.1080/14756366.2022.2140420Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer propertiesBarbara Kaproń0Anita Płazińska1Wojciech Płaziński2Tomasz Plech3Department of Clinical Genetics, Medical University of Lublin, Lublin, PolandDepartment of Biopharmacy, Medical University of Lublin, Lublin, PolandDepartment of Biopharmacy, Medical University of Lublin, Lublin, PolandDepartment of Pharmacology, Medical University of Lublin, Lublin, PolandAbstractMolecular docking of a large set of thiosemicarbazide-based ligands resulted in obtaining compounds that inhibited both human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase-1 (IDO1). To the best of our knowledge, these compounds are the first dual inhibitors targeting these two enzymes. As both of them participate in the anticancer response, the effect of the compounds on a panel of cancer cell lines was examined. Among the cell lines tested, lung cancer (A549) and melanoma (A375) cells were the most sensitive to compounds 1 (IC50=0.23 µg/ml), 2 (IC50=0.83 µg/ml) and 3 (IC50=0.25 µg/ml). The observed activity was even 90-fold higher than that of etoposide, with selectivity index values reaching 125. In-silico simulations showed that contact between 1-3 and human DNA topoisomerase II was maintained through aromatic moieties located at limiting edges of ligand molecules and intensive interactions of the thiosemicarbazide core with the DNA fragments present in the catalytic site of the enzyme.https://www.tandfonline.com/doi/10.1080/14756366.2022.2140420Antiproliferative activitydocking simulationsimmunotherapythiosemicarbazide derivatives |
| spellingShingle | Barbara Kaproń Anita Płazińska Wojciech Płaziński Tomasz Plech Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties Journal of Enzyme Inhibition and Medicinal Chemistry Antiproliferative activity docking simulations immunotherapy thiosemicarbazide derivatives |
| title | Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties |
| title_full | Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties |
| title_fullStr | Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties |
| title_full_unstemmed | Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties |
| title_short | Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties |
| title_sort | identification of the first in class dual inhibitors of human dna topoisomerase iiα and indoleamine 2 3 dioxygenase 1 ido 1 with strong anticancer properties |
| topic | Antiproliferative activity docking simulations immunotherapy thiosemicarbazide derivatives |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2140420 |
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