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Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential
Christoph Selg1, Vuk Gordić2, Tamara Krajnović2
1Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany.
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.
Insights
Novel carborane-based prodrugs show potent anti-cancer activity against colon cancer cell lines. A unique amidine compound demonstrated significant cell viability reduction, suggesting a promising new therapeutic avenue.
Area of Science:
- Medicinal Chemistry
- Drug Design
- Oncology
Background:
- Diclofenac is a non-steroidal anti-inflammatory drug with known anti-cancer properties.
- Carboranes offer a unique scaffold for drug development.
- Prodrug strategies can enhance drug delivery and efficacy.
Purpose of the Study:
- To design and synthesize novel diclofenac-based carborane-substituted prodrugs.
- To evaluate the anti-cancer potential of these compounds against colon cancer cell lines.
- To investigate the mechanism of action of the most potent compounds.
Main Methods:
- Synthesis of four carborane-derivatized oxindoles and one zwitterionic amidine.
- In vitro testing of anti-cancer activity against MC38, HCT116, and HT29 cell lines.
- Assays for cyclooxygenase (COX-1 and COX-2) inhibition, cell division, apoptosis, and reactive oxygen/nitrogen species (ROS/RNS) depletion.
Main Results:
- Diclofenac and carborane-substituted oxindoles showed no cytotoxicity.
- Dichlorophenyl-substituted oxindole exhibited moderate anti-cancer activity.
- The amidine compound displayed potent anti-cancer activity in the low micromolar range.
- Compound 3 significantly inhibited cell division and induced moderate apoptosis in MC38 cells, with ROS/RNS depletion.
- Carborane compounds showed varied anti-cancer effects, potentially via COX-dependent and independent pathways.
Conclusions:
- Carborane-based prodrugs represent a promising strategy for developing new anti-cancer therapies.
- The novel amidine compound warrants further investigation as a potential colon cancer therapeutic.
- The anti-cancer effects may involve multiple pathways beyond COX inhibition.
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