2D‐ and 3D‐Quantitative Structure‐Activity Relationship Studies for a Series of Phenazine N,N’‐Dioxide as Antitumour Agents

Abstract

Hypoxic regions of tumours are associated with increased resistance to radiation and chemotherapy. Nevertheless, hypoxia has been used as a tool for specific activation of some antitumour prodrugs, named bioreductive agents. Phenazine dioxides are an example of such bioreductive prodrugs. Our 2D-quantitative structure activity relationship studies established that phenazine dioxides electronic and lipophilic descriptors are related to survival fraction in oxia or in hypoxia. Additionally, statistically significant models, derived by partial least squares, were obtained between survival fraction in oxia and comparative molecular field analysis standard model (r² = 0.755, q² = 0.505 and F = 26.70) or comparative molecular similarity indices analysis-combined steric and electrostatic fields (r² = 0.757, q² = 0.527 and F = 14.93), and survival fraction in hypoxia and comparative molecular field analysis standard model (r² = 0.736, q² = 0.521 and F = 18.63) or comparative molecular similarity indices analysis-hydrogen bond acceptor field (r² = 0.858, q² = 0.737 and F = 27.19). Categorical classification was used for the biological parameter selective cytotoxicity emerging also good models, derived by soft independent modelling of class analogy, with both comparative molecular field analysis standard model (96% of overall classification accuracy) and comparative molecular similarity indices analysis-steric field (92% of overall classification accuracy). 2D- and 3D-quantitative structure-activity relationships models provided important insights into the chemical and structural basis involved in the molecular recognition process of these phenazines as bioreductive agents and should be useful for the design of new structurally related analogues with improved potency.

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

“…Our research group has developed and described phenazine 5,10-dioxide derivatives, as selective agents in hypoxic conditions, from which leaders emerged to treat solid tumors [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Particularly, the overexpression of reductase enzymes participates in biological processes by bioreducting compounds with these N -oxide functions.…”

Electroreduction of Derivatives of N,N'-Dioxides of Phenazine and Quinoxaline in Nonaqueous Media and in the Presence of Proton Donors of Medium Strength

“…At the end of electrolysis, the solution was diluted by a factor of 3-5 with water, the precipitate was filtered and dried. The extracted products were analyzed by 1 Н NMR spectroscopy and mass spectrometry.…”

“…The derivatives of N,N′-dioxides of phenazine and quinoxaline are often considered [1][2][3] as the potential medicinal drugs for curing "hard" tumors with the large hypoxic regions where almost no oxygen can penetrate. Under hypoxia conditions, the cells become resistant to radiation and chemotherapy.…”

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

“…In order to avoid this problem SN30000 ( B , Figure ) has been developed and studied in its ability to act as selective hypoxic cytotoxin . In addition, N ‐oxide derivatives belonging to quinoxaline 1,4‐dioxide and phenazine 5,10‐dioxide families have been evaluated mainly as in vitro selective hypoxic cytotoxins and in some cases, for example for quinoxaline 1,4‐dioxides, in vivo studies were done to probe their effectiveness . In reference to synthetic phenazine 5,10‐dioxides some interesting derivatives were identified by us, i. e. derivatives C and 1 (Figure ), which displayed the best in vitro potency, concentration that gives 1% cell survival in hypoxia.…”