Transferring the Concept of Multinuclearity to Ruthenium Complexes for Improvement of Anticancer Activity

Abstract

Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC 50 values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.

Anticancer activity of multinuclear arene ruthenium complexes coordinated to dendritic polypyridyl scaffolds

“…The first complex evaluated of this kind was [Ru(benzene)(metronidazole)Cl 2 ] which presented a higher activity compared to the antitumour drug metronidazole itself [13]. More recently the hydrophilic phosphine-containing [Ru(p-cymene)(pta)Cl 2 ] (pta = 1,3,5-triaza-7-phosphatricyclo [3.3.1.1] [16] and ethylendiamine [17] ligands were found to be relatively inactive in vitro, whereas pyrone-derived dinuclear complexes have demonstrated in vitro anticancer activity in the low lM range [18][19][20]. The in vitro anticancer activity of the latter compounds are determined to some extent by their lipophilicity [20], and their mononuclear analogues are not active in cell cultures [21] 2+ [23] have been studied in vitro or in vivo for their activity, and some show promise against cisplatin-resistant cell lines.…”

Mass spectrometry as a powerful tool to study therapeutic metallodrugs speciation mechanisms: Current frontiers and perspectives

“…[84][85][86] In the cases of angiotensin and bombesin, the fragmentation was performed using CID, while additional data were obtained using ECD. The results showed that the primary binding sites of such complexes were methionine and histidine residues, with phenylalanine being a potential secondary site The potential interaction of Ru(II), [87][88][89][90] Ru(III) [90,91] and dinuclear Ru(II) [92] anticancer agents towards oligonucleotides was also studied by ESI-MS. For instance, RAPTA derivatives as well as their osmium analogues were investigated for their reactivity towards a 14-mer single stranded oligonucleotide. [89] The results showed that while RAPTA-C gives rise to Ru-oligonucleotide mono-adducts following detachment of the arene, the osmium analogue forms both mono-and bis-adducts with maintenance of the arene moiety.…”

Dinuclear Gold(III) Complexes as Potential Anticancer Agents: Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-Bridged Derivatives~!2009-12-08~!2010-01-15~!2010-03-25~!

“…In recent years, a rather common strategy in the field of "Anticancer metal based drugs" has been the design of dinuclear or polynuclear derivatives [11]. Such a "multinuclear" strategy produced promising results in the case of anticancer platinum drugs [12] and was recently extended to nonplatinum compounds such as ruthenium compounds [13].…”