Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential
Abstract In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique z...
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Nature Portfolio
2024-12-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-81414-x |
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| author | Christoph Selg Vuk Gordić Tamara Krajnović Antonio Buzharevski Markus Laube Aleksandr Kazimir Peter Lönnecke Mara Wolniewicz Menyhárt B. Sárosi Jonas Schädlich Jens Pietzsch Sanja Mijatović Danijela Maksimović-Ivanić Evamarie Hey-Hawkins |
| author_facet | Christoph Selg Vuk Gordić Tamara Krajnović Antonio Buzharevski Markus Laube Aleksandr Kazimir Peter Lönnecke Mara Wolniewicz Menyhárt B. Sárosi Jonas Schädlich Jens Pietzsch Sanja Mijatović Danijela Maksimović-Ivanić Evamarie Hey-Hawkins |
| author_sort | Christoph Selg |
| collection | DOAJ |
| description | Abstract In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways. |
| format | Article |
| id | doaj-art-56c1fabc039140efa0db165d9588b9fa |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-56c1fabc039140efa0db165d9588b9fa2025-08-20T02:39:40ZengNature PortfolioScientific Reports2045-23222024-12-0114111810.1038/s41598-024-81414-xRe-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potentialChristoph Selg0Vuk Gordić1Tamara Krajnović2Antonio Buzharevski3Markus Laube4Aleksandr Kazimir5Peter Lönnecke6Mara Wolniewicz7Menyhárt B. Sárosi8Jonas Schädlich9Jens Pietzsch10Sanja Mijatović11Danijela Maksimović-Ivanić12Evamarie Hey-Hawkins13Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig UniversityDepartment of Immunology, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of BelgradeDepartment of Immunology, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of BelgradeDepartment of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig UniversityDepartment of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-RossendorfInstitute for Drug Discovery, Leipzig UniversityDepartment of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig UniversityDepartment of Chemistry and Mineralogy, Institute of Organic Chemistry, Leipzig UniversityDepartment of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig UniversityDepartment of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-RossendorfDepartment of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-RossendorfDepartment of Immunology, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of BelgradeDepartment of Immunology, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of BelgradeDepartment of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig UniversityAbstract In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29). The tests showed that diclofenac and the carborane-substituted oxindoles exhibited no cytotoxicity, the dichlorophenyl-substituted oxindole had moderate anti-cancer activity, while with the amidine this effect was strongly potentiated with activity mapping within low micromolar range. Compound 3 abolished the viability of selected colon cancer cell line MC38 preferentially through strong inhibition of cell division and moderate apoptosis accompanied by ROS/RNS depletion. Our findings suggest that carborane-based prodrugs could be a promising direction for new anti-cancer therapies. Inhibition assays for COX-1 and COX-2 revealed that while diclofenac had strong COX inhibition, the re-engineered carborane compounds demonstrated a varied range of anti-cancer effects, probably owing to both, COX inhibition and COX-independent pathways.https://doi.org/10.1038/s41598-024-81414-xCyclooxygenase inhibitorsCarboranesNon-steroidal anti-inflammatory drugCancerDrug repurposing |
| spellingShingle | Christoph Selg Vuk Gordić Tamara Krajnović Antonio Buzharevski Markus Laube Aleksandr Kazimir Peter Lönnecke Mara Wolniewicz Menyhárt B. Sárosi Jonas Schädlich Jens Pietzsch Sanja Mijatović Danijela Maksimović-Ivanić Evamarie Hey-Hawkins Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential Scientific Reports Cyclooxygenase inhibitors Carboranes Non-steroidal anti-inflammatory drug Cancer Drug repurposing |
| title | Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential |
| title_full | Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential |
| title_fullStr | Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential |
| title_full_unstemmed | Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential |
| title_short | Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential |
| title_sort | re design and evaluation of diclofenac based carborane substituted prodrugs and their anti cancer potential |
| topic | Cyclooxygenase inhibitors Carboranes Non-steroidal anti-inflammatory drug Cancer Drug repurposing |
| url | https://doi.org/10.1038/s41598-024-81414-x |
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