Artículo de revista
Structural modifications on the phenazine N,N′-dioxide-scaffold looking for new selective hypoxic cytotoxins
Fecha
2010Registro en:
European Journal of Medicinal Chemistry, Volumen 45, Issue 11, 2018, Pages 5362-5369
02235234
17683254
10.1016/j.ejmech.2010.08.061
Autor
Lavaggi, María Laura
Nieves, Marcos
Cabrera, Mauricio
Olea Azar, Claudio
López de Ceráin, Adela
Monge, Antonio
Cerecetto, Hugo
González, Mercedes
Institución
Resumen
We have identified phenazine 5,10-dioxides as prodrugs for antitumour therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here, we investigated some structural modifications in order to find new selective hypoxic cytotoxins and to establish the structural requirements for adequate activity. Three different chemical-series were prepared and the clonogenic survival of V79 cells on aerobic and anaerobic conditions was determined. Electrochemical- and DNA-interaction studies were done for the most relevant derivatives. The new fluoro-derivative 7-fluoro-2-aminophenazine 5,10-dioxide displayed selective toxicity towards hypoxic V79 cells having adequate hypoxic cytotoxicity ratio (HCR = 6.8) and being the most potent hypoxic cytotoxins (P = 2.5 μM) described for this family of bioreductive agents. The reduction potential of the N-oxide moiety in this new fluoro-derivative was in the range for adequate bioreduction property. According to the fluorescence studies, t