Journal Article

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

Pietzsch, Jens, Maksimović-Ivanić, Danijela, Buzharevski, Antonio, Laube, Markus, Hey-Hawkins, Evamarie, Gordić, Vuk, Selg, Christoph, Lönnecke, Peter, Sárosi, Menyhárt B., Mijatović, Sanja, Kazimir, Aleksandr, Schädlich, Jonas, Krajnović, Tamara, Wolniewicz, Mara

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 631/154/309/2144 / 692/308/153 / Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Apoptosis - drug effects / Boranes - chemistry / Boranes - pharmacology / Cancer / Carboranes / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Colonic Neoplasms - drug therapy / Colonic Neoplasms - pathology / Cyclooxygenase 1 - metabolism / Cyclooxygenase 2 - metabolism / Cyclooxygenase inhibitors / Cyclooxygenase Inhibitors - chemistry / Cyclooxygenase Inhibitors - pharmacology / Diclofenac - chemistry / Diclofenac - pharmacology / Drug Design / Drug repurposing / HCT116 Cells / HT29 Cells / Humanities and Social Sciences / Humans / Mice / multidisciplinary / Non-steroidal anti-inflammatory drug / Prodrugs - chemistry / Prodrugs - pharmacology / Reactive Oxygen Species - metabolism / Science / Science (multidisciplinary)