Novel asymmetric naphthalenediimide-polyamines conjugates as anticancer agents.

As the number of cases of cancer increases worldwide there is a need to develop better and more selective anticancer agents. Naphtalenediimide (NDI) scaffold is present in a wide number of anticancer agents which interact with DNA preferentially as intercalators (Brana and Ramos, 2001). Additionally, some derivatives characterized by this core have been optimized to exhibit bis-threading intercalating ability (Nojima et al., 2003), and to stabilize G-quadruplex DNA structure (Balasubramanian and Neidle, 2009). Recently, we reported a new series of NDI derivatives as antiproliferative agents (Tumiatti et al., 2009). These last compounds were characterized by NDI scaffold properly functionalized with two basic side chains. The most interesting compound was 1, characterized by one methoxy group on the two aromatic rings. Polyamine (PA) analogues have been extensively investigated for their potential pharmacological applications in different diseases, especially as anticancer agents (Casero and Woster, 2009; Wallace, 2009). Furthermore, a polyamine transport system (PTS) was identified and several anthracene-polyamines conjugates demonstrated the ability to hit cancer cells selectively characterized by PTS (Palmer and Wallace, 2009). Very recently, symmetric NDI-PA conjugates were published showing an interesting biological profile as anticancer agents (Wang et al., 2012). On this basis new asymmetric NDI-polyamines conjugates (NDI-PA) were designed (see general structure in Figure 1) with the aim to improve the anticancer activity and/or selectivity of 1 through PTS interaction and transport inside the cells to reach several key targets including DNA. PAs architecture was altered and ranged from diamine to triamine and tetraamine systems. The novelty of such derivatives is represented by their asymmetric structure, which can offer the possibility to design future new conjugates characterized by NDI scaffold and PA chain, coupled with different anticancer pharmacophores. All data related to the antiproliferative activity of these derivatives along with new insights on their molecular mechanisms, PTS interaction, and G-quadruplex stabilization will be shown and discussed.