title: Cytotoxic, mutagenicity, and genotoxicity effects of guanylhydrazone derivatives.
abstract: Several studies have reported that guanylhydrazones display a variety of desirable biological properties, such as antihypertensive, antibacterial, and antimalarial behaviour. They furthermore promote anti-pneumocystosis and anti-trypanosomiasis, exhibit antitumor activity, and show significant cytotoxicity against cancer cell lines. In this work, we have evaluated the cytotoxicity, mutagenicity, and genotoxicity of two guanylhydrazones derivatives, (E)-2-[(2,3-dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (2,3-DMeB) and (E)-2-[(3,4-dimethoxyphenyl) methylene] hydrazine carboxymidamide hydrochloride (3,4-DMeB), in different biological models. Both 2,3-DMeB and 3,4-DMeB induce weak cytotoxic and mutagenic effects in bacteria and yeast. The genotoxicity of these compounds was determined in a fibroblast cell line (V79) using alkaline comet assay, as well as a modified comet assay with bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (EndoIII). Both guanylhydrazone derivatives induced DNA damage. Treatment of V79 cells with EndoIII and FPG proteins demonstrated a significant effect of 2,3-DMeB and 3,4-DMeB with respect to oxidized bases. In addition, the derivatives induced a significant increase in the frequency of micronucleated cells at high doses. The antifungal and anti-trypanosomal properties of these guanylhydrazone derivatives were also evaluated, and the obtained results suggest that 2,3-DMeB is more effective than 3,4-DMeB. The biological activity of 2,3-DMeB and 3,4-DMeB may thus be related, at least in part, to their oxidative potential, as well as to their ability to interact with DNA. Considering the previously reported in vitro antitumor activity of guanylhydrazone derivatives in combination with the lack of acute toxicity and the fact that DNA damage is only observed at high doses should render both compounds good candidates for in vivo studies on antitumor activity.
authors.affiliation: Department of Biophysics/Biotechnology Center, Federal University of Rio Grande do Sul, Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil; Laboratory of Genetic Toxicology, Lutheran University of Brazil, Farroupilha 8001, 92425-900, Canoas, RS, Brazil.
authors.forename: Valéria Rodrigues
authors.initials: VR
authors.lastname: Pinhatti
authors.affiliation: Laboratory of Genetic Toxicology, Lutheran University of Brazil, Farroupilha 8001, 92425-900, Canoas, RS, Brazil. Electronic address: juliana.silva@ulbra.br.
authors.forename: Juliana
authors.initials: J
authors.lastname: da Silva
authors.affiliation: Department of Chemistry, Federal University of Pampa, General Osório 900, 96400-10, Bagé, RS, Brazil.
authors.forename: Tales Leandro Costa
authors.initials: TL
authors.lastname: Martins
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Sarmento Leite 245, 90050-170, Porto Alegre, RS Brazil, Brazil.
authors.forename: Dinara Jaqueline
authors.initials: DJ
authors.lastname: Moura
authors.affiliation: Department of Biophysics/Biotechnology Center, Federal University of Rio Grande do Sul, Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil.
authors.forename: Renato Moreira
authors.initials: RM
authors.lastname: Rosa
authors.affiliation: Department of Biophysics/Biotechnology Center, Federal University of Rio Grande do Sul, Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil.
authors.forename: Izabel
authors.initials: I
authors.lastname: Villela
authors.affiliation: Department of Microbiology, Federal University of Rio Grande do Sul, Sarmento Leite 500, 90050-170, Porto Alegre, RS Brazil, Brazil.
authors.forename: Cheila Denise Ottonelli
authors.initials: CD
authors.lastname: Stopiglia
authors.affiliation: Department of Biochemistry and Immunology, ICB, Federal University of Minas Gerais, Antônio Carlos 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Selma
authors.initials: S
authors.lastname: da Silva Santos
authors.affiliation: Department of Microbiology, Federal University of Rio Grande do Sul, Sarmento Leite 500, 90050-170, Porto Alegre, RS Brazil, Brazil.
authors.forename: Maria Lúcia
authors.initials: ML
authors.lastname: Scroferneker
authors.affiliation: Department of Biochemistry and Immunology, ICB, Federal University of Minas Gerais, Antônio Carlos 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Carlos Renato
authors.initials: CR
authors.lastname: Machado
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre, Sarmento Leite 245, 90050-170, Porto Alegre, RS Brazil, Brazil.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
authors.affiliation: Department of Biophysics/Biotechnology Center, Federal University of Rio Grande do Sul, Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil. Electronic address: pegas@cbiot.ufrgs.br.
authors.forename: João Antonio Pêgas
authors.initials: JA
authors.lastname: Henriques
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity; D002460:Cell Line; D020552:Comet Assay; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D006835:Hydrazones / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D014344:Trypanocidal Agents / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D006835:Hydrazones; D009153:Mutagens; D014344:Trypanocidal Agents
keywords: Cytotoxicity; Genotoxicity; Guanylhydrazone derivatives; Saccharomyces cerevisiae; Salmonella typhimurium; V79 cells