Selective Hypoxia-Cytotoxin 7-Fluoro-2-Aminophenazine 5,10-Dioxide: Toward Candidate-to-Drug Stage in the Drug-Development Pipeline

Abstract

7-Fluoro-2-aminophenazine 5,10-dioxide, 1, has displayed in vitro bioreductive selective cytotoxicity, which could acts towards tumors containing hypoxic regions. In this work, we describe some preclinical studies of compound 1 confirming its in vivo antitumor activity. The synthesis of compound 1 was scaled up to 3 g improving the micro-scale yield. Some drug-like properties for compound 1 were theoretically-predicted and others, i.e. aqueous-solubility and toxicity -mutagenicity, in vivo chromosomal-aberrations and ip acute LD50-, were experimentally confirmed. Antitumoral activity was studied in mice bearing hypoxic 4T1-breast-tumor by assessing evolution of the tumor sizes, animal-survival and bio-chemical/hematological. Compound 1 in vivo efficacy, with the absence of systemic toxicity, was confirmed. Results highlight the potential of 7-fluoro-2-aminophenazine 5,10-dioxide as promissory therapeutic agentfor solid tumors.