Oxo-heterocyclic fused naphthalimides as antitumor agents: Synthesis and biological evaluation

Three series of novel oxo-heterocyclic fused naphthalimide derivatives (8a–8f, 13a–13d, 17a–17d) were prepared. The newly-synthesized compounds, and their thio-heterocyclic fused analogs (1a–1c, 2a–2d, 3a–3c) exhibited potent antiproliferative activity correlated well with their structure. Further research demonstrated that all the representative compounds 13a, 2a and 17a, 3a showed strong inhibition activity to topo II similarly with amonafide, and also potent topo I inhibition activity, which was seldom reported before for naphthalimide derivatives. Preliminary exploration proved their DNA sequence preference. In all, dual topo I/topo II inhibition and DNA sequence preference might contribute to enhancing tumor selectivity and overcoming drug resistance.

Three series of oxo-heterocyclic fused naphthalimides were prepared. The relatively weak DNA intercalators were potent dual topo I/topo II inhibitors.Figure optionsDownload as PowerPoint slideHighlights
► Novel oxo-heterocyclic fused naphthalimides were synthesized.
► Potent antiproliferative activities and preliminary SAR were observed.
►  Naphthalimides are proved to be dual topo I/II inhibitors.