Lavaggi, M.L. (María L.)
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- 3-Trifluoromethylquinoxaline N,N’-Dioxides as Anti-trypanosomatid Agents. Identification of Optimal Anti-T. cruzi Derivatives and Mechanism of Action Studies(American Chemical Society, 2011) Boiani, L. (L.); Vera-De-Bilbao, N. (Ninfa); Aldana, I. (Ignacio); Torres, E. (Enrique); Gonzalez, M. (Mercedes); Benitez, D. (Diego); Di-Maio, R. (Rossanna); Lopez-de-Cerain, A. (Adela); Pérez-Silanes, S. (Silvia); Hernández, P. (Paola); Monge, A. (Antonio); Serna, E. (Elva); Moreno-de-Viguri, E. (Elsa); Cerecetto, H. (Hugo); Lavaggi, M.L. (María L.); Ferreira, M.E. (María E.); Cabrera, M. (Mauricio); Yaluff, G. (Gloria); Solano, B. (Beatriz)As a fourth approach of quinoxaline N,N’-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing substituent in the 2-, 3-, 6-, and 7-positions rendered the most active compounds. With regard to these features, and taking in account their mammal-cytotoxicity, some trifluoromethylquinoxaline N,N’-dioxides have been proposed as candidates for further clinical studies. Consequently, mutagenicity and in vivo analyses were performed with one of the most promising derivatives. In addition, with regard to the mechanism of action studies, it was demonstrated that mitochondrial dehydrogenases are involved in the anti-T. cruzi activity of the most active derivatives.
- 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.
- Novel phenazine 5,10-dioxides release OH in simulated hypoxia and induce reduction of tumour volume in vivo(Hindawi Publishing Corporation, 2011) Pintos, C. (Cristina); Cascante, M. (Marta); Gonzalez, M. (Mercedes); Pérez-Arredondo, C. (Carolina); Lopez-de-Cerain, A. (Adela); Rodríguez, J. (Jorge); Pachon, G. (Gisela); Pacheco, J.P. (José Pedro); Olea-Azar, C. (Claudio); Monge, A. (Antonio); Cerecetto, H. (Hugo); Lavaggi, M.L. (María L.); Raymondo, S. (Stella); Cabrera, M. (Mauricio)Phenazine 5,10-dioxides (PDOs) are a new class of bioreductive cytotoxins, which could act towards tumours containing hypoxic regions. The PDOs selective-hypoxic bioreduction was probed in vitro; however, the mechanism of action has not been completely explained. Besides, PDOs in vivo antitumour activities have not been demonstrated hitherto. We study the mechanism of hypoxic/normoxic cytotoxicity of PDO representative members. Electron spin resonance is used to confirm (•)OH production, alkaline comet assay to determine genotoxicity, and gel electrophoresis and flow cytometry to analyze DNA fragmentation and cell cycle distribution. Chemically induced rat breast tumours are employed to evaluate in vivo activities. For the most selective cytotoxin, 7(8)-bromo-2-hydroxyphenazine 5,10-dioxide (PDO1), exclusive hypoxic (•)OH production is evidenced, while for the unselective ones, (•)OH is produced in both conditions (normoxia and simulated hypoxia). In normoxia (Caco-2 cells), PDO1 induces cell-cycle arrest and DNA fragmentation but does not significantly induce apoptosis neither at IC(50) nor IC(80). No difference in the comet-assay scores are observed in normoxia and simulated hypoxia being the unselective 2-amino-7(8)-bromophenazine 5,10-dioxide (PDO2) the most genotoxic. The in vivo efficacy with the absence of systemic toxicity of PDO1 and PDO2 is checked out. Results from this study highlight the potential of PDOs as new therapeutics for cancer.