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 agent for solid tumors.

Development and Evaluation of 2-Amino-7-Fluorophenazine 5,10-Dioxide Polymeric Micelles as Antitumoral Agents for 4T1 Breast Cancer

“…After 5 days of inoculation, tumor diameters were measured daily with a sterile vernier caliper. The two tumor diameters, width and length, were measured and the tumor volume (V) was calculated using the following equation: V = (width 2 × length)/2 [ 15 , 54 , 55 , 56 , 57 ].…”

“…If the metabolization is by reduction of the N- oxide to amines, via two electrons, it leads to an agent that could interact with biomolecules like DNA, RNA polymerases and topoisomerases or both and the amine-protonation promotes an exclusively confined in the diseased tissue due to the acidic pH of the tumor cell microenvironment in the hypoxic conditions [ 13 , 14 ]. Derivatives of phenazine dioxides, such as the compound 2-amino-7-fluorophenazine 5,10-dioxide (FNZ), have low aqueous solubility (208 µg/mL) that prevents their selective action at the tumor level, their oral administration, parenteral and transdermal [ 11 , 15 , 16 ]. Thus, its clinical use would be restricted, due to the low biodistribution of the body aqueous milieu.…”

Glucosylated Polymeric Micelles Actively Target a Breast Cancer Model

“…The two diameters of the tumor, width ( W ) and length ( L ), were perpendicular to each other and cover the largest portion of the tumor in each direction. Tumor volume ( T V ) was calculated using Equation (3) [ 66,67 ] Ex vivo fluorescence imaging analysis of the accumulation of CUR‐loaded PMs was carried out by the i.v. injection of PMs in the tail vein of female BALB/c mice with induced 4T1 tumor (mean weight of 26.0 ± 1.9 g).…”

“…Biodistribution of Curcumin-Loaded Pristine and Glucosylated Polymeric Micelles: 4T1 breast tumors were developed in female BALB/c mice at the Reagent Unit for Experiment Biomodels (URBE, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay) as previously described. [58,66,67] The average weight of BALB/c (5 to 7 weeks old) was between 23.6 and 25.2 g, housed in wire mesh cages at 20 ± 2°C with 12 h artificial light-dark cycles. Animals were fed ad libitum to standard pellet diet and water and were used after a minimum of 3 days acclimation to the housing conditions.…”

“…The two diameters of the tumor, width (W) and length (L), were perpendicular to each other and cover the largest portion of the tumor in each direction. Tumor volume (T V ) was calculated using Equation (3) [66,67]…”