Ruthenium complexes show promise when submitted to toxicological safety tests using alternative methodologies.

Autor: Teixeira TM; Instituto de Ciências Biológicas, Universidade Federal de Goiás (UFG), CEP 74045-155, Goiânia, GO, Brazil; Aquatic Ecology and Toxicology, Center for Organismal Studies, University of Heidelberg, D-69117, Heidelberg, Germany. Electronic address: thallitam.ciencia@hotmail.com., Arraes IG; Instituto de Ciências Biológicas, Universidade Federal de Goiás (UFG), CEP 74045-155, Goiânia, GO, Brazil., Abreu DC; Instituto de Ciências Biológicas, Universidade Federal de Goiás (UFG), CEP 74045-155, Goiânia, GO, Brazil., Oliveira KM; Departamento de Química, Universidade Federal de São Carlos (UFSCar), CP 676, CEP 13565-905, São Carlos, SP, Brazil; Departamento de Química, ICEB, Universidade Federal de Ouro Preto (UFOP), CEP 35400-000, Ouro Preto, MG, Brazil., Correa RS; Departamento de Química, ICEB, Universidade Federal de Ouro Preto (UFOP), CEP 35400-000, Ouro Preto, MG, Brazil., Batista AA; Departamento de Química, Universidade Federal de São Carlos (UFSCar), CP 676, CEP 13565-905, São Carlos, SP, Brazil., Braunbeck T; Aquatic Ecology and Toxicology, Center for Organismal Studies, University of Heidelberg, D-69117, Heidelberg, Germany., de Paula Silveira Lacerda E; Instituto de Ciências Biológicas, Universidade Federal de Goiás (UFG), CEP 74045-155, Goiânia, GO, Brazil. Electronic address: elacerda@ufg.br.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Apr 15; Vol. 216, pp. 113262. Date of Electronic Publication: 2021 Feb 15.
DOI: 10.1016/j.ejmech.2021.113262
Abstrakt: The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF 6 and (2) [Ru(Lap)(dppb)(phen)]PF 6 , where Law = Lawsone, Lap = Lapachol, dppb = 1,4-bis(diphenylphosphine)butane and phen = 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van der Waals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L -1 , with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (1) showed sublethal effects such as decreased blood circulation and heartbeat rate, which were less pronounced than with complex (2). In contrast to complex 2, which caused lethality even before 48h, complex (1) did not cause the death of the embryos at concentrations up to (2.0 mg L -1 ). Complex (2) also lead to a delay in the embryo. Cell based in vitro methods thus proved able to provide specific toxicological data, allowing a significant reduction in ∖animal experimentation. Given that in vitro tests cannot completely replace animal tests, the use of less advanced developmental stages such as zebrafish embryos, which - at least in the European Union - are not regarded protected, could be shown to be an excellent alternative for testing with, e.g., mammals.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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