Many ruthenium complexes were tested as potential anticancer

Many ruthenium complexes were tested as potential anticancer agents and two complexes, namely NAMI-A (trans-[imH] [RuCl4(dmso-S)(im)]; im, imidazole) and KP1019 (trans-[indH][RuCl4(ind)2]; ind, indazole) have successfully entered clinical trials [27], [28]. NAMI-A is selectively active against metastases of solid tumors [29], while KP1019 is active against colorectal tumors [30]. It also has been shown that inhibition of enzyme activities is of great importance in the mode of action of ruthenium-containing compounds. In contrast with the omnipresent DNA, various proteins are overexpressed in cancerous vegfr2 thus making them valuable potential targets for drugs with high selectivity. This, together with the modest price of starting material RuCl3, its low toxicity and its predictable and established synthetic chemistry as well as the high number of possible structural modifications of the octahedral metal coordination scaffold in comparison with organic frameworks makes ruthenium highly attractive metal for the development of chemotherapeutics with novel modes of action [31], [32]. Meggers developed organoruthenium compounds as protein kinase inhibitors which are air- and water-stable [33]. Dyson and coworkers evaluated a series of ruthenium(II)-arene (RAPTA) compounds for the ability to inhibit thioredoxin reductase and cathepsin B, two possible targets for anticancer metallodrugs. Herein, the cleavage of the metal–chloride bonds is observed, in some cases followed by subsequent loss of the pta ligand [34]. Ruthenium compounds as protease cathepsin K inhibitors were investigated by Kodanko and coworkers. They demonstrated for the first time that intracellular light-activated enzyme inhibition is possible using ruthenium caging approaches. These photoactivated inhibitors have potencies in the nanomolar range and no apparent toxicity [35]. Furthermore, ruthenium polypiridyl complexes were discovered to inhibit human telomerase and topoisomerase, show comparable cytotoxicities as cisplatin [36], inhibit acetylcholineesterase and prevent amyloid-β aggregation thus making them promising candidates for anticancer and antialzheimer drug development [37]. In recent years, our group has investigated the possible application of organoruthenium derivatives of clinically used drugs as potential anticancer agents [38]. Application of metal-based drugs in non-oncology applications is gaining importance and some interesting examples have been described for Ru(II) complexes [39]. Our complexes were for example tested for activity against tropical diseases [40] and fungal diseases [41]. Additionally, their affinity for potential macromolecular targets such as DNA, transport proteins was studied and their inhibitory action against various enzymes has also been tested (human topoisomerase, cathepsins, aldo–keto reductases) [40], [42], [43], [44]. Even though research in the past decade has been focused towards organometallic half-sandwich Ru(II) complexes [45], [46], it has been shown that the π-bonded aromatic ligands are not essential for the anticancer activity of ruthenium complexes [47]. Therefore the activities of Ru(II) complexes with face-capping ligand like sulfur macrocycle 1,4,7-trithiacyclononane ([9]aneS3) substituting η6-arene ligands have also been investigated [42], [48], [49]. Since the exact mechanism of action of different types of ruthenium complexes is not fully understood and while it is possible that they hit multiple targets, it is important to investigate interactions with various potential targets to gain insight into the possible modes of action. In this paper, we present the continuation of our research on the physicochemical and biological properties of Ru(II) complexes with different ligands with the general formulas [Ru([9]aneS3)(dmso)(N,N- or N,O-donor ligand)](PF6)2 and [(η6-p-cymene)RuCl(O,O-ligand)]Cl. We evaluated the inhibitory action of Ru(II) complexes against the iron dependent human 15-LOX-1 enzyme using the recombinant enzyme and an enzyme activity assay based on the UV-absorbance of the reaction product. Both newly synthesized compounds were characterised by NMR, X-ray diffraction and other standard physicochemical methods. The stability of the complexes in DMSO and aqueous solution was studied by the means of NMR spectroscopy. The enzyme inhibition and enzyme kinetics were also determined.