Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential

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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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Scientific Reports
Subjects:
Cyclooxygenase inhibitors
Carboranes
Non-steroidal anti-inflammatory drug
Cancer
Drug repurposing
Online Access:https://doi.org/10.1038/s41598-024-81414-x
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Summary: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.
ISSN:2045-2322

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