Disruption of the Glutathione Defence System by Inhibition of the Glutathione S-Transferase Using Redox-Active Copper Complexes

• Applicant: Igor Esarev
• Subject Area: Biological and Biomimetic Chemistry ; Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570516057

The proposed project describes a novel approach for a development of cancer therapy by evaluation of dual-functional compounds that simultaneously inhibit glutathione S-transferase (GST) and oxidize intracellular glutathione (GSH). Cancer cells often overexpress components of the glutathione system — specifically GST and GSH — to maintain redox balance and evade the cytotoxic effects of chemotherapy. This project aims to selectively disrupt this protective mechanism using copper(II) terpyridine complexes as catalysts of GSH oxidation that covalently linked to known GST inhibitors, such as ethacrynic acid (EA) or 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX). These conjugates are designed to "anchor" to the active site of GST enzymes via the inhibitor moiety, while the redox-active copper(II) complex catalyzes oxidation of GSH molecules approaching the active site of the enzyme, which eventually results in excessive production of reactive oxygen species (ROS). This targeted disruption of redox homeostasis is expected to selectively trigger apoptosis in cancer cells while sparing healthy cells with lower GST/GSH activity. The work programme includes the synthesis and full chemical characterization of a small library of such conjugates (up to 10 compounds), followed by thorough physicochemical, electrochemical, and biological evaluation. This includes studies of ROS generation, GSH depletion, GST inhibition, and apoptosis induction in a range of cancer cell lines with elevated GST expression. Selectivity will be confirmed by comparison with healthy cell lines. Mechanistic studies include fluorescent imaging, flow cytometry, western blotting, and enzymatic activity assays to confirm cellular targets and death pathways. Lead compounds will be further studied in advanced models including 3D tumor spheroids and, at a later stage, in vivo in a mouse xenograft model in collaboration. The following project will represent an example of a dual-targeting strategy with a promising new direction in anticancer drug development, addressing the urgent need for more effective treatments against resistant cancers. By combining molecular precision with catalytic redox activity, the proposed approach could open new avenues in personalized and selective cancer therapy.

• DFG Programme: WBP Position