Discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induce ferroptosis and inhibit triple-negative breast cancer metastasis.

Carbonic anhydrase IX (CAIX) is an attractive target for therapeutic intervention in many hypoxic tumors. Herein, we described the discovery of novel thiourea benzenesulfonamides based 1,8-naphthalimide derivatives as carbonic anhydrase IX inhibitors that induced ferroptosis and inhibited triple-negative breast cancer metastasis. One of the representative compounds, 11o, effectively inhibited CA IX enzymatic activity and displayed high selective for CA IX over CA II. Molecular docking study and molecular dynamics simulations were also performed to gain insights into the binding interactions of 11o in the binding pocket of CAIX and complex stability. Satisfyingly, this compound exhibited superior antitumor activities against MDA-MB-231 cells under hypoxia than normoxic conditions and surpassed reference compound SLC-0111. Mechanism studies revealed that 11o effectively inhibited topoisomerase I activity, induced cell apoptosis and ferroptosis and suppressed cell migration in MDA-MB-231 cells. Notably, in vivo assays results demonstrated that 11o exerted efficient antitumor activity and significant anti-metastasis potency in a xenograft model of highly metastatic murine breast cancer 4 T1 cells. These findings suggest that 11o may serve as a potential candidate for combating triple-negative breast cancer metastasis.