Design, Synthesis, and biological evaluation of naphtalene diimides derivatives as anticancer agent

The search for novel chemotherapeutic agents and approaches to cancer treatment is an active research field stimulated by the discovery of new biological targets and by the possibility of obtaining new drugs without serious and undesirable side effects. Several anticancer agents have been developed so far based on different mechanism of action; despite this, intercalator agents still remain an interesting class of molecules to focus on. In particular, in the literature there are several examples of Naphthalimmide and 1,4,5,8-Naphtalentetracaboxylic diimide derivatives as intercalating and anticancer agents. It is well-known that, at physiological pH, protonated polyamines interact strongly with the phosphate residues of DNA. Therefore, the inclusion of these basic functionalities, on an intercalating moiety, may improve the interaction with DNA structure. Recently, we reported on the design and synthesis of substituted Naphtalen(di)immides as anticancer agents (1). Among the several developed compounds, 1 and 2 were the most interesting derivatives showing the ability to bind DNA, trigger caspase activation, cause accumulation of p53 protein, down-regulate the survival kinase AKT, cause a decrease of ERK1/2 and, inhibit ERK’s phosphorylation. The aim of the present work is to further investigate the promising biological profile of 1 and 2, and the role of the 2-methoxy substituents on the benzyl moieties, For this purpose several analogues, with different substituents on the two aromatic rings, were synthesized evaluated for their antiproliferative activity. This research was supported by grants from MUR, the University of Bologna, and Polo Scientifico-Didattico di Rimini. We thank the National Cancer Institute for the anticancer assays. (1) Tumiatti, V., et al. J. Med. Chem. 2009, 52, 7873-7.