Ru^II(p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo

Abstract

Ruthenium­(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru­(p-cymene)­(L-N,N)­Cl]­[CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis­(pyridin-2-yl)­quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru­(p-cymene)­(Cl)­(μ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV–vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru­(p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru­(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log K b) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.

Anticancer Potential of Diiron Vinyliminium Complexes

“…The final complexes [ 2 – 19 ]CF 3 SO 3 , synthesized at ambient temperature and purified by chromatography without the need of an inert atmosphere, were isolated in good to high yields (52–96 %) as air stable solid materials. Concerning the choice of the counteranion, it should be noted that a variety of ionic metal complexes with triflate as counteranion have been proposed to date as possible anticancer drugs, and, among them, Ru II arene complexes with bidentate N,N‐ligands were investigated in vivo showing no significant toxicity …”

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

“…Anti-tumor effects when found in essential oils from Nigella sativa [295]. Ruthenium 11 (p-Cymene) complexes were effective and selective against several cancers [296][297][298].…”

“…p-Cymene is a common ligand for ruthenium, proposed as a potential alternative to platinum-based chemotherapies. Ruthenium II (p-Cymene) complexes have been suggested as effective and selective anticancer candidates under various forms for different cancer types [296][297][298].…”

Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases

“…On the other hand, p-cymene can be utilized to synthesize novel and efficient metal anti-tumor drugs, ruthenium complexes. These complexes displayed lack of cytotoxicity in vivo as well as in vitro, and successfully exhibited anti-proliferative capacity associated with a combined mechanism of apoptosis and autophagy [117,118].…”