A novel 1,8-naphthalimide-piperazine-amidobenzenesulfonamide derivative targets carbonic anhydrase IX to induce ferroptosis, apoptosis and autophagy in colorectal cancer cells†

Carbonic anhydrases (CAs) are crucial for cancer cells to survive in hypoxia. Here we show that our newly synthesised 1,8-naphthalimide-piperazine-amidobenzenesulfonamide derivative, namely compound Q, specifically targets CA IX and causes cell death in colorectal cancer. Compound Q stably binds to the zinc atom in the active pocket of CA IX and selectively inhibits the activity of this enzyme. It kills SW480 cells under normoxic and hypoxic conditions, with an IC₅₀ of 17.03 ± 1.09 μM and 10.90 ± 0.46 μM, respectively. The inhibitory effect of compound Q against CA IX activity is better under hypoxic conditions and it has low toxicity on normal colon with an IC₅₀ of 38.83 ± 1.98 μM. Compound Q also inhibits tumour growth in the colorectal cancer SW480 xenograft model and it shows no adverse effects on nude mice body weight. Our analyses also demonstrate that compound Q induces ferroptosis, apoptosis and autophagy in colorectal cancer and we believe that these are the main mechanisms by which it promotes cell death in this cancer. Taken together, our data indicate that compound Q is a potent and selective CA IX inhibitor that is promising for the treatment of colorectal cancer.