Tags

Type your tag names separated by a space and hit enter

RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo.
Inorg Chem. 2018 Nov 05; 57(21):13150-13166.IC

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 Kb) 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.

Authors+Show Affiliations

Departamento de Química & Centro de Investigaciones Científicas Avanzadas (CICA) , Universidade da Coruña , 15008 A Coruña , Spain.Área Departamental de Engenharia Química , ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa , Rua Conselheiro Emídio Navarro, 1 , 1959-007 Lisboa , Portugal. Centro de Química Estrutural, Complexo 1, Instituto Superior Técnico , Universidade de Lisboa , Av. Rovisco Pais , 1049-001 Lisboa , Portugal.Centro de Química Estrutural, Faculdade de Ciências , Universidade de Lisboa , Campo Grande, 1749-016 Lisboa , Portugal.UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia , Universidade Nova de Lisboa , Campus de Caparica, 2829-516 Caparica , Portugal.UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia , Universidade Nova de Lisboa , Campus de Caparica, 2829-516 Caparica , Portugal.Centro de Ciências e Tecnologías Nucleares (C2TN), Instituto Superior Técnico , Universidade de Lisboa , E.N. 10 (km 139.7) , 2695-066 Bobadela LRS , Portugal.Neurover Group, Centro de Investigacións Científicas Avanzadas (CICA) and Department of Biology , Universidade da Coruña , 15008 A Coruña , Spain. Department of Cell and Developmental Biology , University College London , Gower Street , London WC1 6BT , U.K.Neurover Group, Centro de Investigacións Científicas Avanzadas (CICA) and Department of Biology , Universidade da Coruña , 15008 A Coruña , Spain.Departamento de Química & Centro de Investigaciones Científicas Avanzadas (CICA) , Universidade da Coruña , 15008 A Coruña , Spain.Departamento de Química & Centro de Investigaciones Científicas Avanzadas (CICA) , Universidade da Coruña , 15008 A Coruña , Spain.Departamento de Química & Centro de Investigaciones Científicas Avanzadas (CICA) , Universidade da Coruña , 15008 A Coruña , Spain.Departamento de Química & Centro de Investigaciones Científicas Avanzadas (CICA) , Universidade da Coruña , 15008 A Coruña , Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30339386

Citation

Lenis-Rojas, Oscar A., et al. "RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates With No Toxicity in Vivo." Inorganic Chemistry, vol. 57, no. 21, 2018, pp. 13150-13166.
Lenis-Rojas OA, Robalo MP, Tomaz AI, et al. RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo. Inorg Chem. 2018;57(21):13150-13166.
Lenis-Rojas, O. A., Robalo, M. P., Tomaz, A. I., Carvalho, A., Fernandes, A. R., Marques, F., Folgueira, M., Yáñez, J., Vázquez-García, D., López Torres, M., Fernández, A., & Fernández, J. J. (2018). RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo. Inorganic Chemistry, 57(21), 13150-13166. https://doi.org/10.1021/acs.inorgchem.8b01270
Lenis-Rojas OA, et al. RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates With No Toxicity in Vivo. Inorg Chem. 2018 Nov 5;57(21):13150-13166. PubMed PMID: 30339386.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RuII(p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo. AU - Lenis-Rojas,Oscar A, AU - Robalo,M Paula, AU - Tomaz,Ana Isabel, AU - Carvalho,Andreia, AU - Fernandes,Alexandra R, AU - Marques,Fernanda, AU - Folgueira,Mónica, AU - Yáñez,Julián, AU - Vázquez-García,Digna, AU - López Torres,Margarita, AU - Fernández,Alberto, AU - Fernández,Jesús J, Y1 - 2018/10/19/ PY - 2018/10/20/pubmed PY - 2018/11/13/medline PY - 2018/10/20/entrez SP - 13150 EP - 13166 JF - Inorganic chemistry JO - Inorg Chem VL - 57 IS - 21 N2 - 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 Kb) 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. SN - 1520-510X UR - https://www.unboundmedicine.com/medline/citation/30339386/RuII_p_cymene__Compounds_as_Effective_and_Selective_Anticancer_Candidates_with_No_Toxicity_in_Vivo_ L2 - https://doi.org/10.1021/acs.inorgchem.8b01270 DB - PRIME DP - Unbound Medicine ER -