A novel Ru(II)-mitoxantrone metallodrug : double mechanism of action for anticancer applications

Since the clinical application of the leading cisplatin anticancer drug, a great deal of work has been devoted to find new compounds showing a comparable antitumor activity but with reduced side effects. In this context, many organic, inorganic and organometallic compounds have been synthesized and their behaviour towards biological targets has been investigated. Among them, some half-sandwich organometallic Ru(II)-complexes display a similar or even better antitumor activity than Pt(II)-metallopharmaceuticals and they are expected to show reduced toxicity[1] as a consequence of a different mechanism of action (i.e. inhibition of overexpressed enzymatic processes).[2] In this communication, we present the new dinuclear [(h6-p-Cy)2Ru2mitoxantronato]Cl2 (1) system obtained by reacting mitoxantrone, a DNA intercalating anticancer drug currently used in the treatment of lymphomas and metastatic breast cancer, with the organometallic [(h6-p-Cy)2Ru2Cl4] system. The binding of two [(p-Cy)Ru] metal fragments to both sides of mitoxantrone leads to an exo- hexadentate N,N,O,N’,N’,O’ bridging mode with the concomitant deprotonation of the aromatic amino groups as evidenced by the single crystal X-ray diffraction structure determination (Figure 1). Taking into account the DNA-intercalating features of mitoxantrone, we have studied the possible effect of the interaction of 1 on the DNA structure by means of different biophysical methods, namely, UV-vis, circular dichroism and competitive binding with ethidium bromide (Figure 2). The results prove that Ru binding to mitoxantrone do not significantly hamper its DNA intercalating ability, inducing important conformational changes in this biomolecule. In addition, we have also studied the interaction of 1 with additional biological targets showing that this system readily reacts with amino acids (S-donor) with a concomitant inhibition of cathepsin type enzymes, which are involved in the exacerbated metabolism of many cancer cell types. The above mentioned biological assays are indicative that this novel metal complex has a double mechanism of action that may eventually leads to an important antitumor activity. Current work is carried out in order to evaluate the possible in vitro cytotoxic activity of this system towards different tumour cell lines.