Synthesis and study of antiproliferative, antitopoisomerase II, DNA-intercalating and DNA-damaging activities of arylnaphthalimides

et al.A series of arylnaphthalimides were designed and synthesized to overcome the dose-limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafide's biological activities.We gratefully acknowledge the financial support from Spanish Ministry of Science and Innovation (SAF 2009-13296-C02-01 and SAF 2012-37344-C03-01 to A.E.B. and SAF 2009-13296-C02-02 and SAF 2012-37344-C03-02 to L.F.P.), Instituto de Salud Carlos III (PS09/00106 and PI12/00280 to F.M.), and the EU Research Potential (FP7-REGPOT-2012-CT2012-316137-IMBRAIN). All projects to principal investigators are also co-founded by the European Regional Development Fund (ERDF). P.Q.E. thanks Gobierno de Chile for a predoctoral fellowship. J.G-L. thanks Spanish Ministry of Education for a predoctoral fellowship (AP2009-2511).Peer Reviewe