Selg Christoph, Gordić Vuk, Krajnović Tamara, Buzharevski Antonio, Laube Markus, Kazimir Aleksandr, Lönnecke Peter, Wolniewicz Mara, Sárosi Menyhárt B, Schädlich Jonas, Pietzsch Jens, Mijatović Sanja, Maksimović-Ivanić Danijela, Hey-Hawkins Evamarie
Department of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Leipzig University, Deutscher Platz 5, 04103, Leipzig, Germany.
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.
Sci Rep. 2024 Dec 16;14(1):30488. doi: 10.1038/s41598-024-81414-x.
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.
在本研究中，我们通过重新审视基于双氯芬酸的碳硼烷取代前药，研究了一种新型抗癌药物设计方法。重新设计的化合物将坚固的碳硼烷支架与羟吲哚骨架相结合，产生了四种碳硼烷衍生的羟吲哚和一种具有巢式簇的独特两性离子脒。我们测试了这些前药对小鼠结肠腺癌（MC38）、人结肠直肠癌（HCT116）和人结肠腺癌（HT29）的抗癌潜力。测试表明，双氯芬酸和碳硼烷取代的羟吲哚没有细胞毒性，二氯苯基取代的羟吲哚具有中等抗癌活性，而对于脒，这种作用在低微摩尔范围内通过活性图谱得到了强烈增强。化合物3通过强烈抑制细胞分裂和中度凋亡并伴随着ROS/RNS消耗，优先消除了选定的结肠癌细胞系MC38的活力。我们的研究结果表明，基于碳硼烷的前药可能是新抗癌疗法的一个有前景的方向。对COX-1和COX-2的抑制试验表明，虽然双氯芬酸具有强烈的COX抑制作用，但重新设计的碳硼烷化合物表现出不同程度的抗癌作用，这可能是由于COX抑制和非COX依赖性途径共同作用的结果。
