2. Academic Validation
  3. 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

  • Sci Rep. 2024 Dec 16;14(1):30488. doi: 10.1038/s41598-024-81414-x.
Christoph Selg 1,  Vuk Gordić 2,  Tamara Krajnović 2,  Antonio Buzharevski 3,  Markus Laube 4,  Aleksandr Kazimir 5,  Peter Lönnecke 1,  Mara Wolniewicz 6,  Menyhárt B Sárosi 3,  Jonas Schädlich 4 7,  Jens Pietzsch 4 7,  Sanja Mijatović 2,  Danijela Maksimović-Ivanić 2,  Evamarie Hey-Hawkins 8
Affiliations

Affiliations

  • 1 Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany.
  • 2 Department of Immunology, Institute for Biological Research "Siniša Stanković" - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, 11108, Serbia.
  • 3 Department of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Leipzig University, Johannisallee 29, 04103, Leipzig, Germany.
  • 4 Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstraße 400, 01328, Dresden, Germany.
  • 5 Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany.
  • 6 Department of Chemistry and Mineralogy, Institute of Organic Chemistry, Leipzig University, Johannisallee 29, 04103, Leipzig, Germany.
  • 7 Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstraße 4, 01069, Dresden, Germany.
  • 8 Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany. hey@uni-leipzig.de.
PMID: 39681576 DOI: 10.1038/s41598-024-81414-x
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.

Keywords

Cancer; Carboranes; Cyclooxygenase inhibitors; Drug repurposing; Non-steroidal anti-inflammatory drug.

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