Novel Ru(II)-bipyridine/phenanthroline-lapachol complexes as potential anti-cancer agents

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De Grandis, Rone Aparecido ; Costa, Analu Rocha ; Ferreira Moraes, Carlos Andre ; Sampaio, Natalia Zaneti ; Cerqueira, Igor Henrique ; Marques, Wellington Garcia ; Mundin Guedes, Adriana Pereira ; de Araujo-Neto, Joao Honorato ; Pavan, Fernando Rogerio ; Demidoff, Felipe Cerqueira ; Netto, Chaquip Daher ; Batista, Alzir Azevedo ; Resende, Flavia Aparecida

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 237, p. 12-pg., 2022-12-01.

Abstract

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 (H-1, C-13), 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. (AU)

• FAPESP's process: 16/22429-7 - Toxicogenetics evaluation and study of antiproliferative response mechanisms of ruthenium-based metallodrugs containing naphthoquinones ligands in tumor cells growing in conventional and 3D systems
• Grantee: Rone Aparecido de Grandis
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/15850-0 - X-ray diffraction as a tool in potential drug development
• Grantee: Eduardo Ernesto Castellano
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/16278-9 - Study of the genotoxicological potential and permeation assay with Caco-2 cells of metallic complexes with promising biological activities
• Grantee: Flávia Aparecida Resende Nogueira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/14561-8 - Study in vitro and in vivo of Ru(II) phosphine complexes with anticancer activities
• Grantee: Alzir Azevedo Batista
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/04876-4 - Studies on structure & activity of RuII / arene / mercaptoligants complexes against cancer
• Grantee: João Honorato de Araujo Neto
• Support Opportunities: Scholarships in Brazil - Post-Doctoral