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(L 1 ) 2 - Cu(L 12 ) 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(L 4 ) 2 and Cu(L 10 ) 2 were reduced to Fenton-like Cu + by glutathione depletion, and the resulting Cu + catalyzed the generation of highly toxic hydroxyl radicals from excess H 2 O 2 . Simultaneously, Cu(L 4 ) 2 and Cu(L 10 ) 2 could decrease the catalase activity to restrain H 2 O 2 transfer to H 2 O for enhanced chemodynamic therapy (CDT). These induced mitochondrial dysfunctions and endoplasmic reticulum stress to induce T24 cell apoptosis. In addition, Cu(L 4 ) 2 and Cu(L 10 ) 2 inhibited autophagy flux to promote cell apoptosis. Cu(L 4 ) 2 and Cu(L 10 ) 2 demonstrated strong tumor inhibition ability in the T24 xenograft model. Moreover, Cu(L 10 ) 2 showed higher antitumor activity and a better safety profile than the CDT agent Cu1 . Cu(L 10 ) 2 exhibited excellent pharmacokinetic properties. Collectively, Cu(L 4 ) 2 and Cu(L 10 ) 2 could be developed as potential CDT candidates for cancer treatment.