👤 Santos FC

For the first time, we herein report on the syntheses of two new Ru(II)/bipyridine/phenanthroline complexes containing lapachol as ligand: complex (1), [Ru (bipy)₂(Lap)]PF₆ and complex (2), [Ru(Lap)(phen)₂]PF₆, where bipy = 2,2'-bipyridine and ph en = 1,10-phenanthroline; Lap = lapachol (2-hydroxy-3-(3-methylbut-2-en-1- yl)naphthalene-1,4-dione). The complexes were synthesized and characterized by elemental analyses, molar conductivity, mass spectrometry, ultraviolet-visible and infrared spectroscopies, nuclear magnetic resonance (¹H, ¹³C), and single crystal X-ray diffraction, for complex (2). In addition, in vitro cytotoxicity was tested against six cancer cells: A549 (lung carcinoma); DU-145 (human prostate carcinoma); HepG2 (human hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma); MDA-MB-231 (human breast adenocarcinoma); Caco-2 (human colorectal adenocarcinoma), and against two non-cancer cells, FGH (human gingival normal fibroblasts) and PNT-2 (prostate epithelial cells). Complex (1) was slightly more toxic and selective than complex (2) for all cell lines, except against the A549 cells, where (2) was more potent than complex (1). The complexes induced an increase in the reactive oxygen species, and the co-treatment with N-acetyl-L-cysteine remarkably suppressed the ROS generation and prevented the reduction of cell viability, suggesting that the cytotoxicity of the complexes is related to the ROS-mediated pathway. Further studies indicated that the complexes may bind to DNA via minor groove interaction. Our studies also revealed that free Lap induces gene mutations in Salmonella Typhimurium, nevertheless, the complexes demonstrated the absence of genotoxicity by the Ames test. The present study provides a relevant contribution to understanding the anti-cancer potential and genetic toxicological events of new ruthenium complexes containing the lapachol molecule as a ligand. Show less

The preparation of two new Ru(II)/diphosphine complexes containing Lapachol (Lap) and Lawsone (Law): (1) [Ru(Lap)(dppm)₂]PF₆ and (2) [Ru(Law)(dppm)₂]PF₆, where dppm = bis(diphenylphosphino)methane, is reported here. The complexes were synthetized and fully characterized by elemental analyses, molar conductivity, UV-Vis, IR, ³¹P{¹H}, ¹H and ¹³C NMR, and the crystal structure of the complex (1) was determined by X-ray diffraction. Complexes (1) and (2) showed high in vitro cytotoxicity against four cancer cells (MDA-MB-231, MCF-7, A549 and DU-145), with IC₅₀ values in the micromolar range (0.03 to 2.70 μM). Importantly, complexes (1) and (2) were more active than the cisplatin, the drug used as a reference in the cytotoxic assays. Moreover, complex (1) showed high selectivity to triple-negative breast cancer cells (MDA-MB-231). Studies of the mechanism of action in MDA-MB-231 cancer cells showed that complex (1) inhibits cell migration, colony formation, and induces cell cycle arrest and apoptosis by activation of the mitochondrial pathway through the loss of mitochondrial membrane potential (ΔΨm). Furthermore, complex (1) induces ROS (Reactive Oxygen Species) generation in MDA-MB-231 cells, which can cause DNA damage. Finally, complexes (1) and (2) interact with DNA by minor grooves and show a moderate interaction with BSA (Bovine Serum Albumin), with the involvement of hydrophobic interactions. Essentially, Ru(II)/diphosphine-naphthoquinone complexes have remarkable cytotoxic effects with high selectivity to triple-negative breast cancer (MDA-MB-231) and could be promising anticancer candidates for cancer treatment. SYNOPSIS: The naphthoquinones Lapachol and Lawsone can form new ruthenium compounds with promising anticancer properties. Show less

A new family of eight ruthenium(II)-cyclopentadienyl bipyridine derivatives, bearing nitrogen, sulfur, phosphorous and carbonyl sigma bonded coligands, has been synthesized. Compounds bearing nitrogen bonded coligands were found to be unstable in aqueous solution, while the others presented appropriate stabilities for the biologic assays and pursued for determination of IC50 values in ovarian (A2780) and breast (MCF7 and MDAMB231) human cancer cell lines. These studies were also carried out for the [5: HSA] and [6: HSA] adducts (HSA=human serum albumin) and a better performance was found for the first case. Spectroscopic, electrochemical studies by cyclic voltammetry and density functional theory calculations allowed us to get some understanding on the electronic flow directions within the molecules and to find a possible clue concerning the structural features of coligands that can activate bipyridyl ligands toward an increased cytotoxic effect. X-ray structure analysis of compound [Ru(η(5)-C5H5)(bipy)(PPh3)][PF6] (7; bipy=bipyridine) showed crystallization on C2/c space group with two enantiomers of the [Ru(η(5)-C5H5)(bipy)(PPh3)](+) cation complex in the racemic crystal packing. Show less

Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. Show less

A novel water soluble organometallic compound, [RuCp(mTPPMSNa)(2,2'-bipy)][CF3SO3] (TM85, where Cp=η(5)-cyclopentadienyl, mTPPMS=diphenylphosphane-benzene-3-sulfonate and 2,2'-bipy=2,2'-bipyridine) is presented herein. Studies of interactions with relevant proteins were performed to understand the behavior and mode of action of this complex in the biological environment. Electrochemical and fluorescence studies showed that TM85 strongly binds to albumin. Studies carried out to study the formation of TM85 which adducts with ubiquitin and cytochrome c were performed by electrospray ionization mass spectrometry (ESI-MS). Antitumor activity was evaluated against a variety of human cancer cell lines, namely A2780, A2780cisR, MCF7, MDAMB231, HT29, PC3 and V79 non-tumorigenic cells and compared with the reference drug cisplatin. TM85 cytotoxic effect was reduced in the presence of endocytosis modulators at low temperatures, suggesting an energy-dependent mechanism consistent with endocytosis. Ultrastructural analysis by transmission electron microscopy (TEM) revealed that TM85 targets the endomembranar system disrupting the Golgi and also affects the mitochondria. Disruption of plasma membrane observed by flow cytometry could lead to cellular damage and cell death. On the whole, the biological activity evaluated herein combined with the water solubility property suggests that complex TM85 could be a promising anticancer agent. Show less