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

• Published in: European journal of medicinal chemistry Vol. 45; no. 11; pp. 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: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.11.2010; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bioreductive agents; Cancer; Cell Line; Chemistry, Medicinal; Cricetinae; Cytotoxins - chemistry; Cytotoxins - pharmacology; Electrochemistry; General aspects; Hypoxia; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenazine N, N′-dioxides; Phenazines - chemistry; Phenazines - pharmacology; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Phenazine N, N′-dioxides; Bioreductive agents; Cancer; Phenazine N,N '-dioxides; NEUTRAL RED; DRUGS; AGENTS; N-OXIDES; DERIVATIVES; BINDING; CALF THYMUS DNA; Antineoplastic agent; Nitrogen heterocycle; Nitrone; Lung; Cytotoxicity; Selectivity; Bioreductive drug; Structure activity relation; V79-Cell line; Aromatic compound; Mechanism of action; Chemical synthesis; Tumor cell; Oxygen; Rodentia; Reduction potential; Tricyclic compound; Phenazine N,N'-dioxides; Vertebrata; Biological fixation; Electrochemical properties; Mammalia; Cell line; DNA; Hypoxia; Fluorine Organic compounds; Hamster; Aromatic amine
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.08.061

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).