Copper(II) Complexes of Halogenated Quinoline Schiff Base Derivatives Enabled Cancer Therapy through Glutathione-Assisted Chemodynamic Therapy and Inhibition of Autophagy Flux

Twelve new complexes Cu(L¹)₂-Cu(L¹²)₂ were designed and synthesized to improve their chemotherapeutic properties. They showed considerable antiproliferative activity against T24 cancer cells but lower cytotoxicity to human normal cells HL-7702 and WI-38. A mechanism study indicated that Cu(L⁴)₂ and Cu(L¹⁰)₂ were reduced to Fenton-like Cu⁺ by glutathione depletion, and the resulting Cu⁺ catalyzed the generation of highly toxic hydroxyl radicals from excess H₂O₂. Simultaneously, Cu(L⁴)₂ and Cu(L¹⁰)₂ could decrease the catalase activity to restrain H₂O₂ transfer to H₂O for enhanced chemodynamic therapy (CDT). These induced mitochondrial dysfunctions and endoplasmic reticulum stress to induce T24 cell apoptosis. In addition, Cu(L⁴)₂ and Cu(L¹⁰)₂ inhibited autophagy flux to promote cell apoptosis. Cu(L⁴)₂ and Cu(L¹⁰)₂ demonstrated strong tumor inhibition ability in the T24 xenograft model. Moreover, Cu(L¹⁰)₂ showed higher antitumor activity and a better safety profile than the CDT agent Cu1. Cu(L¹⁰)₂ exhibited excellent pharmacokinetic properties. Collectively, Cu(L⁴)₂ and Cu(L¹⁰)₂ could be developed as potential CDT candidates for cancer treatment.