Ruthenium anticancer activity

Berger, I., Hanif, M., Nazarov, A. A., Hartinger, C. G., John, R. O. Kuznetsov, M. L. et al. In Vitro Anticancer Activity and Biologically Relevant Metabolization of Organometallic Ruthenium Complexes with Carbohydrate-Based Ligands. Chemistry Europ. Journal 14, 9046-9057 (2008). 

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

Fig. 11. Molecular structures of (a) fac-[RuCl3(NH3)3], the first reported ruthenium complex with anticancer activity, and (b) NAMI-A and KP1019, two ruthenium compounds currently in clinical trials.

Mendoza-Ferri M-G, Hartinger CG, Eichinger RE, Stolyarova N, Severin K, Jakupec MA, Nazarov AA, Keppler BK (2008) Influence of the spacer length on the in vitro anticancer activity of dinuclear ruthenium-arene compounds. Organometallics 27 2405-2407... 

Kandioller W, Hartinger CG, Nazarov AA, Bartel C, Skocic M, Jakupec MA, Arion VB, Keppler BK (2009) Maltol-derived ruthenium-cymene complexes with tumor inhibiting properties the impact of ligand-metal bond stability on anticancer activity in vitro. Chem-EurJ 15 12283-12291... 

As far as we are aware the first example of a ruthenium(II)-arene compound to be evaluated for anticancer activity was described by Tocher and co-workers in 1992 [18]. The field remained essentially dormant until the explosion in interest led largely by our group and that of Sadler, who has extensively studied ruthenium(II)-arene complexes with ethylenediamine and related ligands, and describes these compounds in the Chapter X in this book. It should be noted that other groups have also contributed to the field as will become clear in the course of this Chapter. 

Fig. 7 Examples of ruthenium(II)-arene and osmium(II)-arene paullone complexes with high in vitro anticancer activity...

Mendoza-Ferri MG, Hartinger CG, Mendoza MA, Groessl M, Egger A, Eichinger RE, Mangrum JB, Farrell NP, Maruszak M, Bednarski PJ, Klein F, Jakupec MA, Nazarov A, Severin K, Keppler BK (2009) Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity. J Med Chem 52 916-925... 

Mattsson J, Govindaswamy P, Renfrew AK, Dyson PJ, Stepnicka P, Suss-Fink G, Therrien B (2009) Synthesis, molecular structure, and anticancer activity of cationic arene ruthenium metallarectangles. Organometallics 28 4350-4357... 

Barry NPE, Zava O, Furrer J, Dyson PJ, Therrien B (2010) Anticancer activity of opened arene ruthenium metalla-assemblies. Dalton Trans 39 5272-5277... 

Figure 8 Further examples of piano-stool ruthenium complexes studied for anticancer activity in vitro.

Ruthenium arenes are another interesting class of organometallics with proven anticancer activity. The most active complex [( 7 -biphenyl)Ru(ethylene-diamine)Cl] 1 (Scheme 11) had an activity comparable to Garboplatin against a human ovarian cancer cell line. " The interaction of this compound with different biomolecules has been studied, and again, DNA has been suggested as the primary target. It is, however, unclear at present... 

Similar systems contacting ruthenium as active antineoplastic agents has been also proposed. Such complex rappresent and efficient and promising alternative to the platinum anticancer agents. ... 

Khan BJk, Aqmand P, Tabassum S, Monari M, Marchetti P, Pettinari C. Organome-taHic ruthenium(II) scorpionate as topo Ila inhibitor in vitro binding studies with DNA, HPLC analysis and its anticancer activity. J Organomet Chem. 2014 771 47-58. 

Recently Clarke et al. have advanced the proposal that antitumor RudDammine complexes may excert their action by redox cycling in the presence of oxygen and a reducing agent with formation of active oxygen species which cleave DNA. The most prominent member of the metal group is cis-DDP. Evidence for electron transfer is provided by electrochemical behavior , radiosensitization" and nephrotoxicity s 2-74, Anticancer activity is displayed by a number of other metals and metalloids in compound form s -- . The possibility exists that the ultimate active forms of the various metals may be the DNA complexes, for example, with copper s and ruthenium . ET and oxy radical formation are known to occur with enzymes that contain copper s . 

Figure 3 A selection of anticancer-active Ruthenium coordination compounds. The compounds NAM FA (1) and NAMl (2), each have an imidazolium as a counter cation a very active compound (3) of the a isomer of a Ru-azpy compound (azpy = 2-phenylazopyridine) and a Ru-terpy compound (4). From these NAMFA has been in clinical trials since 2000.

There continues to be considerable activity in the field of reactions of ruthenium complexes. Interest in a large number of complexes of the [Ru(bipy)3] type remains at a high level, but this interest has in recent months been very much biased toward electron transfer reactions and photophysics, rather than the substitution processes which come within the remit of this review. However, in recent months there has been a marked increase in activity in the area of mechanisms of anticancer activity of ruthenium complexes. This topic has formed the subject of a book, and some relevant complexes appear in later sections, particularly Section 8.4.6. 

---