Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors.

Functional 1,8-naphthalimide derivatives are rapidly developing in the field of anticancer research. Herein, we designed and synthesized a series of naphthalimide derivatives with different substituents. Interestingly, 1,8-naphthalimide derivatives and inhibited a human demethylase FTO (the fat mass and obesity-associated protein). Computer simulation studies further indicated that and entered the FTO's structural domain II binding pocket through hydrophobic and hydrogen bonding interactions. Anticancer mechanism studies showed that and induced DNA damage and autophagic cell death in A549 cells. The high antiproliferative activity of and was further confirmed by 3D multicellular A549 tumor spheroid assays. This study focuses on the cytotoxicity and mode of action of naphthalimide derivatives, which not only have potential anticancer activity but also are potent demethylase inhibitors.