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 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.
Lavaggi
María Laura
ML
Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
Nieves
Marcos
M
Cabrera
Mauricio
M
Olea-Azar
Claudio
C
López de Ceráin
Adela
A
Monge
Antonio
A
Cerecetto
Hugo
H
González
Mercedes
M
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003603:Cytotoxins / Q000737:chemistry* / Q000494:pharmacology*; D004563:Electrochemistry; D000860:Hypoxia; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010619:Phenazines / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D003603:Cytotoxins; D010619:Phenazines; C071996:phenazine di-N-oxide