title: Study of benzo[a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation.
abstract: 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.
authors.affiliation: Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.forename: María de Los Angeles
authors.initials: Mde L
authors.lastname: Aravena
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea-Azar
authors.forename: Adela
authors.initials: A
authors.lastname: López de Ceráin
authors.forename: Antonio
authors.initials: A
authors.lastname: Monge
authors.forename: Gisela
authors.initials: G
authors.lastname: Pachón
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Ana María
authors.initials: AM
authors.lastname: Bruno
authors.forename: Lía I
authors.initials: LI
authors.lastname: Pietrasanta
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D018938:Caco-2 Cells; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000188:drug therapy; D006224:Cricetinae; D004249:DNA Damage; D053938:DNA Fragmentation; D006801:Humans; D010619:Phenazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D010619:Phenazines