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

Author(s)

Teixeira, Thallita Monteiro ^{[1, 2]} ; Arraes, Isabela Gasparini ^[1] ; Abreu, Davi Carvalho ^[1] ; Oliveira, Katia M. ^{[3, 4]} ; Correa, Rodrigo S. ^[4] ; Batista, Alzir A. ^[3] ; Braunbeck, Thomas ^[2] ; Silveira Lacerda, Elisaangela de Paula ^[1]

Affiliation

^[1] Univ Fed Goias UFG, Inst Ciencias Biol, BR-74045155 Goiania, Go - Brazil

^[2] Heidelberg Univ, Ctr Organismal Studies, Aquat Ecol & Toxicol, D-69117 Heidelberg - Germany

^[3] Univ Fed Sao Carlos UFSCar, Dept Quim, CP 676, BR-13565905 Sao Carlos, SP - Brazil

^[4] Univ Fed Ouro Preto UFOP, Dept Quim, ICEB, BR-35400000 Ouro Preto, MG - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 216, APR 15 2021.
• Web of Science Citations: 1

Abstract

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)]PF6 and (2) {[}Ru(Lap)(dppb)(-phen)]PF6, 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 derWaals 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\textbackslash{}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. (C) 2021 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 14/04147-9 - Evaluation of anticancer properties of ruthenium(II)complexes containing lapachol and lawsone bioligands
• Grantee: Katia Mara de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate