Synthesis and dual-action anticancer activity of novel fluorescently monitored naphthalimide monomethyl triazene molecular chimeras

A new facile synthesis, biological evaluation, and ``switchable`` fluorescent properties of novel anticancer molecular hybrids (chimeras) operating through a dual mechanism of action are described. These chimeras consist of DNA intercalating 3-amino 1,8-naphthalimide core (amonafide) and DNA methylating methyl triazene moiety protected with a carbamate group. These two anticancer core structures are bound to each other by means of a self immolative 4‑amino benzyl carbamate linker. The hydrolytic cleavage of the triazene carbamate protecting group and 4-amino benzyl carbamate linker causes activation of both monomethyl triazene and amino naphthalimide counterparts followed by a substantial red-shift in the naphthalimide fluorescence. The chimeric molecules exhibited significantly higher antiproliferative activity in cancer cell lines compared to Amonafide or monomethyl triazene constituents. We utilized the fluorescent properties of chimera to develop a ``photo-switchable`` reporting system to monitor the prodrug activation. Using this approach, we found that the chimera accumulated and was activated at the tumor sites specifically and demonstrated significantly stronger tumor-suppressing activities compared to Amonafide in a xenograft model.

References

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