5-Non-amino aromatic substituted naphthalimides as potential antitumor agents: Synthesis via Suzuki reaction, antiproliferative activity, and DNA-binding behavior

Amonafide is a naphthalimide derivative with antitumor activity and has failed to enter clinical phase III, because of its high-variable and unpredictable toxicity. In order to develop selective, efficient, and safe drugs, applying the 'nonfused' aromatic system strategy, a series of 5-non-amino aromatic substituted naphthalimides as replacement for amonafide were designed and were synthesized from naphthalic anhydride by three steps including bromination, amination, and Pd(PPh₃)₄ catalyzed Suzuki reaction. These new naphthalimide derivatives, except 4b, not only exhibited better activity than amonafide against HeLa and P388D1 cell lines in vitro under the same experimental conditions, but also could avoid the side effect of amonafide due to their structure, which lacks an easy acetylated arylamine at the 5 position. The DNA-binding behavior of the naphthalimide derivatives was also investigated, and the results suggested that they bind to DNA via intercalation and 4a and 4g intercalated into DNA in different fashion.