Study of benzo[ a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation

Benzo[ a]phenazine 7,12-dioxide scaffold has been studied as selective hypoxic cytotoxin and as antiproliferative agents on Caco-2 tumoral cells in normoxia. Electrochemical, DNA-interaction and DNA-damage studies were performed to establish the mode of action. Phenazine 5,10-dioxides are prodrugs f...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2010-06, Vol.18 (12), p.4433-4440
Main Authors: Lavaggi, María Laura, Cabrera, Mauricio, Aravena, María de los Ángeles, Olea-Azar, Claudio, López de Ceráin, Adela, Monge, Antonio, Pachón, Gisela, Cascante, Marta, Bruno, Ana María, Pietrasanta, Lía I., González, Mercedes, Cerecetto, Hugo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - therapeutic use
Benzo[ a]phenazine 7,12-dioxides
Biological and medical sciences
Bioreductive agents
Caco-2 Cells
Cell Hypoxia - drug effects
Cell Line
Colonic Neoplasms - drug therapy
Cricetinae
DNA Damage
DNA Fragmentation
General aspects
Humans
Medical sciences
Pharmacology. Drug treatments
Phenazines - chemical synthesis
Phenazines - chemistry
Phenazines - toxicity
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Summary:Benzo[ a]phenazine 7,12-dioxide scaffold has been studied as selective hypoxic cytotoxin and as antiproliferative agents on Caco-2 tumoral cells in normoxia. Electrochemical, DNA-interaction and DNA-damage studies were performed to establish the mode of action. Phenazine 5,10-dioxides are prodrugs for antitumor therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here we investigate the expanded system benzo[ a]phenazine 7,12-dioxides as selective hypoxic cytotoxin-scaffold. The clonogenic survival of V79 cells on aerobic and anaerobic conditions, conduct us to study antiproliferative activity on Caco-2 tumoral cells in normoxia. Electrochemical, DNA-interaction and DNA-damage studies were performed to establish the mode of action. The results demonstrated the potential biological properties of the studied scaffold being derivatives 6– 10 structural hits for further chemical-modifications to become into therapeutics for solid tumors. Compounds 6 and 8 with cytotoxicity against V79 cells in both conditions (aerobia and anaerobia) were also cytotoxic against Caco-2 tumoral cells in aerobiosis.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2010.04.074