Structural modifications on the phenazine N, N′-dioxide-scaffold looking for new selective hypoxic cytotoxins

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...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2010-11, Vol.45 (11), p.5362-5369
Main Authors: Lavaggi, María Laura, Nieves, Marcos, Cabrera, Mauricio, Olea-Azar, Claudio, López de Ceráin, Adela, Monge, Antonio, Cerecetto, Hugo, González, Mercedes
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Bioreductive agents
Cancer
Cell Line
Cricetinae
Cytotoxins - chemistry
Cytotoxins - pharmacology
Electrochemistry
General aspects
Hypoxia
Magnetic Resonance Spectroscopy
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Phenazine N, N′-dioxides
Phenazines - chemistry
Phenazines - pharmacology
Spectrometry, Mass, Electrospray Ionization
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Summary: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, the DNA-interaction mechanism was especially operative in the phenazine drugs more than in the corresponding prodrugs, phenazine dioxides. [Display omitted] 7-Fluoro-2-aminophenazine 5,10-dioxide was identified as new bioreductive agent (HCR = 6.8, P hypoxia = 2.5 μM).
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2010.08.061