Dinuclear Ru^II(bipy)₂Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation

Abstract

Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)}(μ-L)][CFSO] (L = bptz, 1a) and [{Ru(bipy)}(μ-L)][CFSO] (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)Cl. The complexes were characterized by elemental analysis, mass spectrometry, H andP{H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 μM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells.

The Potential of Zebrafish as a Model Organism for Improving the Translation of Genetic Anticancer Nanomedicines

“…The pathological mechanisms underlying cancer are some of the most challenging processes to understand because of their variety and complexity. Zebrafish is considered a complementary model to murine and other previous models for the study of the genetic basis of cancer and for the evaluation of carcinogenic and novel antitumoral compounds in drug discovery [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ].…”

“…As mentioned in Section 4 , zebrafish is widely used for the evaluation of the adverse effects of drugs, and to determine the activity of antitumor compounds [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. It could also be used to determine the preclinical toxicity of nanocarriers for gene delivery purposes.…”

“…The rate of morphological changes is one of the endpoints used to generate dose response curves [ 141 , 142 ]. The toxicity of several types of nanoparticles, mainly inorganic nanoparticles, has already been determined in zebrafish using this test [ 68 , 104 , 127 , 143 , 144 ]. One important parameter for toxicity evaluation is the hatching efficiency because nanoparticles can interact with hatching enzymes [ 145 ].…”

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

“…In the last year, several ruthenium compounds have been synthetized, and their antiproliferative activities and mechanism of action against several tumors characterized [8,[37][38][39], where cell membrane changes, cell death due to intrinsic apoptosis pathway and/or autophagic pathway, ROS induction, inhibition of topoisomerase I and II might be the cause of their cytotoxicity/antiproliferative activities [8,[39][40][41][42][43][44]…”

“…Cancer cells are known to have a different redox metabolism from normal cells, with augmented levels of intracellular ROS, mostly due to increased metabolic activity and hypoxia, especially in the core of solid tumors [4]. Metal complexes, due to their redox properties, have been shown to disturb cellular redox homeostasis resulting in enhanced levels of oxidative stress prompting cancer cell death [4][5][6][7][8].…”