Synthesis of Novel Nitroxoline Analogs with Potent Cathepsin B Exopeptidase Inhibitory Activity
Tim Van de Walle1, Marina Briand1, Ana Mitrović2
1SynbioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.
Abstract:
Nitroxoline, a well-known antimicrobial agent, has been identified in several independent studies, and on different molecular targets, as a promising candidate to be repurposed for cancer treatment. One specific target of interest concerns cathepsin B, a lysosomal peptidase involved in the degradation of the extracellular matrix (ECM), leading to tumor invasion, metastasis and angiogenesis. However, dedicated optimization of the nitroxoline core is needed to actually deliver a nitroxoline-based antitumor drug candidate. Within that context, 34 novel nitroxoline analogs were synthesized and evaluated for their relative cathepsin B inhibitory activity, their antiproliferative properties and their antimicrobial activity. More than twenty analogs were shown to exert a similar or even slightly higher cathepsin B inhibitory activity compared to nitroxoline. The implemented modifications of the nitroxoline scaffold and the resulting SAR information can form an eligible basis for further optimization toward more potent cathepsin B inhibitors in the quest for a clinical nitroxoline-based antitumor agent.
Insights
Nitroxoline analogs show potential for cancer treatment by inhibiting cathepsin B, a key enzyme in tumor spread. Further optimization of these novel compounds could lead to new antitumor drugs.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Nitroxoline, an antimicrobial, is a promising candidate for cancer treatment repurposing.
- Cathepsin B, involved in tumor invasion and metastasis, is a specific molecular target.
- Optimization of the nitroxoline structure is necessary for developing effective antitumor agents.
Purpose of the Study:
- To synthesize and evaluate novel nitroxoline analogs for cathepsin B inhibition.
- To assess the antiproliferative and antimicrobial activities of these analogs.
- To establish structure-activity relationships (SAR) for further drug development.
Main Methods:
- Synthesis of 34 novel nitroxoline analogs.
- Evaluation of cathepsin B inhibitory activity.
- Assessment of antiproliferative and antimicrobial properties.
Main Results:
- Over twenty analogs demonstrated comparable or improved cathepsin B inhibitory activity versus nitroxoline.
- The study provides valuable SAR data for nitroxoline derivatives.
- Modified nitroxoline scaffolds show potential for enhanced antitumor efficacy.
Conclusions:
- Novel nitroxoline analogs exhibit significant cathepsin B inhibitory activity.
- The synthesized analogs provide a foundation for developing potent, clinical nitroxoline-based antitumor agents.
- Further optimization based on SAR is recommended for advancing nitroxoline repurposing in oncology.
