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Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

2012; Elsevier BV; Volume: 26; Issue: 4 Linguagem: Inglês

10.1016/j.tiv.2012.02.003

1879-3177

Ana Jérsia Araújo, Ademária Aparecida de Souza, Eufrânio N. da Silva Júnior, José Delano Barreto Marinho Filho, Maria Aline Barros Fidelis de Moura, Danilo D. Rocha, Marne Carvalho de Vasconcellos, Cícero O. Costa, Cláudia Pessoa, Manoel Odorico de Moraes, Vı́tor F. Ferreira, Fabiane C. de Abreu, António Pinto, Raquel Carvalho Montenegro, Letícia V. Costa‐Lotufo, Marília Oliveira Fonseca Goulart,

Synthesis and Biological Evaluation

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.