Design, Synthesis, and Biological Evaluation of a Class of TEMPOmodified Naphthalimide Derivatives with Good Selectivity for Tumor Cells

Background: Naphthalimides have been receiving continuous attention for their outstanding performance in treating cancer. However, as a class of cytotoxic anti-tumor agents, their toxic side effects greatly limit their clinical application. Therefore, developing naphthalimide reagents with good selectivity for tumor cells is of great importance. Objective and Methods: A class of TEMPO-modified naphthalimide derivatives substituted with oxygen at the 6-position were designed, synthesized, and evaluated for the anti-tumor activity in vitro against three cancer cell lines (A549, MCF-7, and HeLa) as well as one normal human liver cell line (QSG-7701) by MTT assay. HRMS (or MS) and EPR spectra were used to identify the structures of target compounds. The UV–vis titration absorption spectra were performed to study the interaction between compounds and DNA. Results: The target compounds NT3, NT9, NT10, NT11, and NT12 exhibited moderate inhibition to all the three tested tumor cell lines, while NT1, NT2, and NT4 showed selectivity against A549, All the target compounds did not show measurable activities in QSG-7701, which imply the target compounds are likely to overcome the nonspecific toxicity against normal cells. UV-vis spectra showed this class of compounds could effectively intercalate into DNA and selectively bind to G-C base pairs. Conclusion: A novel class of TEMPO-modified naphthalimide derivatives substituted with oxygen at 6- position and the preliminary discussion on their SARs provide promising opportunities to guide further research on naphthalimide derivatives as anti-tumor agents.