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 nonmalignant 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. Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2115-1) contains supplementary material, which is available to authorized users. & Gary Gellerman garyg@ariel.ac.il & Flavio Grynszpan flaviog@ariel.ac.il 1 Department of Biological Chemistry, Ariel University, 40700 Ariel, Israel 2 Department of Molecular Biology, Ariel University, 40700 Ariel, Israel 3 The Advanced Technologies Center, Sheba Medical Center, 52621 Tel Hashomer, Israel 123 Res Chem Intermed DOI 10.1007/s11164-015-2115-1