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

Chao Ge; Lu Liu; Yanqing Wang; Xiaojiao Di; Xiangjie Luo; Hongke Liu; Yong Qian

doi:10.1021/acsmedchemlett.3c00353

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

ACS Med Chem Lett. 2023 Oct 11;14(11):1551-1557. doi: 10.1021/acsmedchemlett.3c00353. eCollection 2023 Nov 9.

Authors

Chao Ge^{1

2}, Lu Liu¹, Yanqing Wang², Xiaojiao Di¹, Xiangjie Luo¹, Hongke Liu¹, Yong Qian¹

Affiliations

¹ School of Chemistry and Materials Science, Jiangsu Key Laboratory of Biofunctional Materials, Nanjing Normal University, Nanjing 210023, People's Republic of China.
² School of Chemistry and Environmental Engineering, Yancheng Teachers University, Yancheng 224007, People's Republic of China.

Abstract

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 1 and 7 inhibited a human demethylase FTO (the fat mass and obesity-associated protein). Computer simulation studies further indicated that 1 and 7 entered the FTO's structural domain II binding pocket through hydrophobic and hydrogen bonding interactions. Anticancer mechanism studies showed that 1 and 7 induced DNA damage and autophagic cell death in A549 cells. The high antiproliferative activity of 1 and 7 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.