Unprecedented synthesis, in vitro and in vivo anti-cancer evaluation of novel triazolonaphthalimide derivatives

An efficient synthesis method for fusing triazole ring onto the naphthalimide core was described. The anti-cancer activities of the generated triazolonaphthalimide derivatives were evaluated with five cancer cell lines. The compounds generally displayed higher potency than amonafide. 4d,4e carrying two amino side chains showed the strongest cytotoxicities. N-oxide 5, a prodrug of 4a, was designed and synthesized. The agent was expected to be activated under the hypoxic condition in tumor tissue. Compared with 4a, 5 manifested much lower cytotoxicity both in cancer cell lines and human normal cells in the in vitro assays. However, N-oxide 5 performed potent anti-cancer activity in vivo using S-180 sarcoma bearing mice. All the results suggested that 5 was a promising anti-cancer agent.

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► A series of novel triazolonaphthalimide derivatives were synthesized via a new method.
► Cytotoxicity evaluation with five cancer cell lines was conducted and a preliminary SAR was summarized.
► Much higher cytotoxic effects were observed compared with the lead compound amonafide.
► N-oxide 5 as tumor-activated prodrug was further tested with an in vivo tumor model (S-180 cancer cell formed xenograft).