Fine-tuning 8H-quinolines to target resistance in cancer

Cancer remains one of the world`s leading causes of death. Although significant progress has been made in cancer treatment in recent decades, there is still an urgent need for alternative compounds that can overcome drug resistance. Finding new therapeutic strategies against multidrug resistant (MDR) cancers is rather challenging. Our collaborative research between Austrian and Hungarian groups have found that MDR cells are particularly sensitive to certain 8-hydroxyquinoline (8HQ) derivatives and targeting iron homeostasis with MDR-selective compounds can selectively eliminate the these cancer cells. In this project we aim to refine a structure-property-activity relationship of a large library of 8HQ compounds to design more potent derivatives against resistant breast cancer. We will improve the in vivo applicability of these compounds. Different synthetic approaches will be used to optimise the pharmacological properties of the best performing compounds. The MDR-selective toxicity of a focused 8HQ library will be determined using different cancer cell lines. Selected 8HQs will be characterised for pKa values, lipophilicity and membrane permeability to establish a correlation between structure, properties and toxicity. To get a deeper insight into their mechanism of action, we will investigate iron depletion, interaction with the drug efflux pump P-glycoprotein, and reactive oxygen species generation. Solution speciation and redox activity of iron complexes with selected 8HQs will be analysed. Based on these findings, we will synthesise new 8HQ compounds with enhanced MDR selectivity. We will develop organometallic Rh(5-C5Me5) complexes and liposomal nanoformulation will be performed to improve solubility and pharmacological properties. The most promising compounds will be tested in vivo using mouse models of MDR cancer. The final outcome of the project is to obtain compounds that overcome MDR in a preclinical model of therapy resistant breast cancer. The project leverages the complementary expertise of Hungarian chemists and Austrian biologists with state-of-the-art infrastructure and highly recognised scientists in both teams.