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2-Amino-7(8)-fluorophenazine N5,N10-dioxide: Scale-up and Toxicity Evaluation
Carina Sánchez * 1 , Belén Dávila 1 , Joaquín Afonso 2 , Mirel Cabrera 2 , Pablo Cabral 2 , Nicole Lecot 1, 2 , Hugo Cerecetto 1, 2 , Mercedes González * 1
1  Grupo de Química Medicinal, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo, 11400, Uruguay.
2  Área de Radiofarmacia, Facultad de Ciencias, Universidad de la República, Mataojo s/n, Montevideo, 11400, Uruguay.

Published: 01 November 2017 by MDPI AG in 3rd International Electronic Conference on Medicinal Chemistry session Posters
10.3390/ecmc-3-04672
Abstract:

Breast cancer is a solid tumor characterized by a high level of hypoxic areas which are difficult to treat. The rate of this disease in women is elevated, mainly in developing countries since the diagnosis is made in the later stages of the disease. We have developed bioreductive prodrugs under conditions of hypoxia in which the compound 2-amino-7(8)-fluorophenazine N 5 ,N 10 - dioxide (FNZ) stands out as a potent and selective anticancer agent. In order to improve the ADME properties the FNZ was vehiculated in physiological serum:tween (PS:T). This work presents the optimization of the synthesis of FNZ, the evaluation of the mutagenic potential in vitro (AMES test) and the acute toxicity (Up & Down) of free-FNZ and its encapsulated. The optimization of the procedure to scale-up 5 g was done according to the synthesis already described. Washing and drying conditions of the benzofuroxan intermediate and FNZ allowed an overall yield of 60 %, five times higher than the micro-scale procedure. We performed the Ames assay on five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537, TA102) recommended for drug development. The preliminary results indicate that all the systems under study (Free-FNZ, PS:T/FNZ) exhibited mutagenicity in the five Salmonella strains. The most mutagenic system was the free-FNZ being the encapsulation using (PS:T) the least. The acute toxicity showed that the vehiculated FNZ had a maximum dose of 2000 mg/kg of mouse weight. The vehiculated FNZ was not toxic in the Up & Down assay transforming it in a good formulation to be used in vivo studies.


Acknowledgement: The authors want to thank the ANII for financial support.

Keywords: Breast cancer; hypoxic; scale-up; fluorophenazine; Ames test
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