Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward non-malignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies. Graphical Abstract: Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.[Figure not available: see fulltext.]