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Phenazine N,N′-dioxide scaffold as selective hypoxic cytotoxin pharmacophore. Structural modifications looking for further DNA topoisomerase II-inhibition activity
(Royal Society of Chemistry, 2013) Gonda, M. (Mariana); Gonzalez, M. (Mercedes); Nunes, E. (Elia); Lopez-de-Cerain, A. (Adela); Monge, A. (Antonio); Cerecetto, H. (Hugo); Lavaggi, M.L. (María L.); Nieves, M. (Marcos)
Phenazine-5,10-dioxides have been identified as prodrugs for antitumour therapy that undergo hypoxic-selective bioreduction, in the solid tumour cells, to form cytotoxic species. We investigated structural modifications of the phenazine-5,10-dioxide scaffold attempting to find new selective hypoxic cytotoxins with additional ability to inhibit DNA topoisomerase II. Four series of new phenazine-5,10-dioxides aryl-substituted connected by different linkers were prepared. The clonogenic survivals of V79 cells on aerobic and anaerobic conditions were determined, and studies of oxic DNA-interaction and hypoxic DNA topoisomerase II-inhibition, for the most relevant derivatives, were performed. Four new hypoxic-selective cytotoxins were identified at the assayed doses. In some of them were operative the DNA-interaction and/or the inhibition of DNA topoisomerase II. For one of the unselective cytotoxin biotransformation studies were performed on aerobic and anaerobic conditions, explaining the lack of selectivity.