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- Methyl-cyclopentadienyl ruthenium compounds with 2,2 '-bipyridine derivatives display strong anticancer activity and multidrug resistance potentialPublication . Côrte-Real, Leonor; Gonçalves Teixeira, Ricardo; Girio, Patrícia; Comsa, Elisabeta; MORENO, Alexis; Nasr, Rachad; Baubichon-Cortay, Helene; Avecilla, Fernando; Marques, Fernanda; Robalo, Maria Paula; Mendes, Paulo; Prates Ramalho, João P.; Garcia; Falson, Pierre; Valente, AndreiaNew ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(eta(5)-MeCp)(PPh3)(4,4'-R-2,2'-bpy)](+) (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2(1)/c, Ru2 in the triclinic P (1) over bar, and Ru3 in the monoclinic P2(1)/n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.
- Novel ruthenium methylcyclopentadienyl complex bearing a bipyridine perfluorinated ligand shows strong activity towards colorectal cancer cellsPublication . Gonçalves Teixeira, Ricardo; Brás, Ana Rita; Côrte-Real, Leonor; Tatikonda, Rajendhraprasad; Sanches, Anabela; Robalo, Maria Paula; Avecilla, Fernando; Moreira, Tiago; Garcia, M. Helena; Haukka, Matti; Preto, Ana; Valente, AndreiaThree new compounds have been synthesized and completely characterized by analytical and spectroscopic techniques. The new bipyridine-perfluorinated ligand L1 and the new organometallic complex [Ru(η5-MeCp)(PPh3)2Cl] (Ru1) crystalize in the centrosymmetric triclinic space group P
1¯. Analysis of the phenotypic effects induced by both organometallic complexes Ru1 and [Ru(η5-MeCp)(PPh3)(L1)][CF3SO3] (Ru2), on human colorectal cancer cells (SW480 and RKO) survival, showed that Ru2 has a potent anti-proliferative activity, 4–6 times higher than cisplatin, and induce apoptosis in these cells. Data obtained in a noncancerous cell line derived from normal colon epithelial cells (NCM460) revealed an intrinsic selectivity of Ru2 for malignant cells at low concentrations, showing the high potential of this compound as a selective anticancer agent. - Half-sandwich Ru(p-cymene) compounds with diphosphanes: In Vitro and In Vivo evaluation as potential anticancer metallodrugsPublication . Lenis Rojas, Oscar; Robalo, M. Paula; Tomaz, Ana Isabel; Fernandes, Alexandra; Roma-Rodrigues, Catarina; Gonçalves Teixeira, Ricardo; Marques, Fernanda; FOLGUEIRA, MONICA; Yáñez, Julián; Alba-González, Anabel; Salamini-Montemurri, Martin; Pech-Puch, Dawrin; Vázquez-García, Digna; López-Torres, Margarita; Fernandez, Alberto; Fernandez, Jesus J.Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl]-[CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, H-1 and P-31{H-1} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.
- Ruthenium carboranyl complexes with 2,2 '-bipyridine derivatives for potential bimodal therapy applicationPublication . Gonçalves Teixeira, Ricardo; Marques, Fernanda; Robalo, M. Paula; Fontrodona, Xavier; Garcia, M. Helena; Geninatti Crich, Simonetta; Vinas, Clara; Valente, AndreiaRuthenium complexes of carboranyl ligands offer the possibility of dual action (chemo + radiotherapy) that might result in significant clinical benefits. In that frame, we describe herein the development of ruthenium-carboranyl complexes bearing bipyridyl derivatives with the general formula [3-CO-3,3-{kappa(2)-4,4 '-R-2-2,2 '-bipy}-closo-3,1,2-RuC2B9H11] (R = CH3,RuCB1or R = CH2OH,RuCB2). Both compounds crystallized in the monoclinic system, showing the expected three-legged piano stool structure. The ruthenacarboranes are stable in cell culture media and were tested against two cell lines that have shown favorable clinical responses with BNCT, namely melanoma (A375) and glioblastoma (U87).RuCB1shows no cytotoxic activity up to 100 mu M whileRuCB2showed moderate activity for both cell lines. Cell distribution assays showed thatRuCB2presents high boron internalization that is proportional to the concentration used indicating thatRuCB2presents features to be further studied as a potential anticancer bimodal agent (chemo + radiotherapy).