New Directions for Cancer Drug Research of Ruthenium and Rhodium Compounds: Investigation of Cytotoxicities, Mechanisms of Cancer Cell Death, and Cellular Targets

The discovery of the antitumor properties of cisplatin revolutionized the field of medicinal inorganic chemistry and fostered the development of metal-based anticancer drugs, a topic that continues to play a prominent role in chemotherapy. Ruthenium (Ru) compounds are a promising class of anticancer compounds that display improved therapeutic activities, different mechanisms of action, and reduced side-effects as compared to cisplatin. Two ruthenium compounds are being tested in clinical trials for the treatment of cancer malignancies for which platinum drugs are inactive and several other transition metal complexes are in preclinical studies.

In an effort to expand the current state-of-the art in cancer metallotherapeutics, two new classes of ruthenium compounds were synthesized and fully characterized. The first class of complexes is based on Ru(II) coordination compounds of general formula [Ru(N^N)(2)(N^O^(?))][PF(6)], where N^N is a bidentate polypyridyl ligand (bpy = 2,2?-bipyridine; phen = 1,10-phenanthroline) and N^O^(?) is a bidentate nitrogen/oxygen-donor anionic ligand (dphol = dibenzo[a,c]phenazin-10-olate; hbtz = 2-(benzo[d]thiazol-2-yl)phenolate). These molecules exhibit cytotoxic properties that are comparable or more effective than cisplatin against lung cancer cells and were found to induce cellular death through the intrinsic pathway of apoptosis.

The second class of molecules consist of organometallic Ru(II) compounds of formula [Ru(phpy)(N^N_(1))(N^N_(2))][PF_(6)], where phpy is cyclometallated 2-phenylpyridine and N^N are bidentate polypyridyl ligands. The compounds [Ru(phpy)(bpy)(dppn)][PF_(6)] and [Ru(phpy)(pap)(dppn)][PF_(6)] (dppn = benzo[i]dipyrido[3,2-a:2?,3?-c]phenazine; pap = 2-(phenylazo)pyridine) are the most potent members of the series against cervical and ovarian cancer cells and are also active in the multidrug resistant NCI/ADR-RES ovarian cancer cell line. In addition, the compound [Ru(phpy)(biq)(2)][PF(6)] (biq = 2,2?-biquinoline) was shown to exhibit an enhancement of its cytotoxicity when irradiated with red light, results that poise Ru(II) cyclometallated compounds as promising candidates for further development in cancer chemotherapy and photochemotherapy.

Finally, an unprecedented fluorophore-labeled metal-metal bonded dirhodium compound was synthesized and characterized, and its cellular distribution and subcellular localization were studied in living cancer cells by using confocal fluorescence microscopy. This fluorescent compound traverses the cellular membrane of lung cancer cells and localizes in lysosomes and mitochondria. In contrast to previous reports of dirhodium anticancer compounds, it does not target the cell nucleus, supporting the contention that other cellular targets can be reached by tuning the ligand environment around the dirhodium core, opening new avenues for drug design.