Complexes of Ruthenium(II) as Promising Dual-Active Agents Conclusions
Ru complexes are currently objects of considerable attention in therapy, especially as antitumor agents with selective antimetastatic properties and low systemic toxicity. NAMI-A and BOLD-100 are structurally related Ru(III) coordination compounds that have attracted a lot of attention in the medicinal inorganic chemical scientific community for their anticancer activities. Ru(II) complexes have the potential to provide a safer, more-effective, and less-expensive alternative to traditional platinum-based chemotherapy for biomedical applications. Recent studies have been focused towards the synthesis of new analogues of RAED-C and RAPTA-C, which are two Ru(II) complexes that have shown excellent antitumoral activities in both in vitro and in vivo studies. The most interesting results were obtained with complexes bearing the p-cymene moiety, including 1,3,5-triaza-7-phosphaadamantane and triphenylphosphine, as well as with polypyridyl and NHC derivatives. Interesting recent studies have also been focused on complexes bearing more than one transition metal type, such as Cu, Ni, and Se, thereby obtaining high activity effects, also in the nanomolar range, against different cell lines. The challenge is now represented by the discovery of new dual-active drugs that act as anticancer and antiviral agents. Although there are a lot of studies on antitumoral activity, very few studies have been carried out regarding antiviral activity. Interestingly, BOLD-100 has demonstrated activity against SARS-CoV-2, HIV-1, and human adenovirus type 5. Thus, new studies are needed in this direction. The search for effective alternatives to existing transition metal complexes used in therapy or under clinical trials is still a great challenge for scientists. The major goal is represented by the need to overcome the most common limitations, such as the onset of resistance phenomena and severe side effects. The employment of Ru complexes may offer a valid alternative to the most-used platinum drugs because of their lower toxicity, synergistic features, and the ability to overcome drug resistance. The discussed different chemical properties and the versatility of the obtained complexes represent the winning points for the future development and new applications of these complexes as part of a valid therapeutic arsenal.
The demonstrated effectiveness of Ru(II) complexes and, generally, the coordination of Ru(II) with different ligands are vital for their activity and selectivity effects. Thus, future studies should focus on investigating the structure–activity relationships (SARs) in order to establish the role of different functional groups interacting with the ligands in modulating the activity effects. Furthermore, the diffusion across the cell membrane and the possibility to target organelles, such as mitochondria, or important biomolecules, such as DNA and proteins, should be studied in association with the charge or lipophilicity of the considered complexes in order to design and synthetize more nontoxic and selective drugs. Next, it should also be highlighted that a growing trend is being directed toward the design of hybrid complexes, made of Ru complex moieties combined with natural biomolecules or fluorescent probes, whose applications would have a high potential in different research and clinical fields. Finally, one of the major hindrances regarding the development of Ru(II) complexes and their application in clinics is that their mechanisms of action are still poorly investigated and understood, from which the need for in-depth studies is highly desirable.