Abstract
The electrochemical properties of twenty 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives with varying degrees of cytotoxic activity were investigated in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. With one exception, the first reduction of these compounds was found to be reversible or quasireversible and is attributed to reduction of the N-oxide moiety to form a radical anion. The second reduction of the diazine ring was found to be irreversible. Compounds containing a nitro group on the 3-phenyl ring also exhibited a reduction process that may be attributed to that group. There was good correlation between molecular structure and reduction potential, with reduction being facilitated by an enhanced net positive charge at the electroactive site created by electron withdrawing substituents. Additionally, the reduction potential was calculated using two common basis sets, 6-31g and lanl2dz, for five of the test molecules. There was a strong correlation between the computational data and the experimental data, with the exception of the derivative containing the nitro functionality. No relationship between the experimentally measured reduction potentials and reported cytotoxic activities was evident upon comparison of the data.
Highlights
22 of known that some quinoxaline 1,4-di-N-oxide derivatives undergo bioreduction under hypoxic well-known that some quinoxaline 1,4-di-N-oxide derivatives undergo bioreduction under hypoxic conditions, leading to the formation of a radical capable of cleaving DNA [2,3]. The latter may occur conditions, leading to the formation of a radical capable of cleaving DNA [2,3]. The latter may occur via direct abstraction of hydrogen atoms from DNA or production of DNA-cleaving hydroxyl via direct abstraction of hydrogen atoms from DNA or production of DNA-cleaving hydroxyl radicals, radicals, both mechanisms introducing oxidative stress within the target cells
The compounds included in this study are 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide
The compounds included in this study are 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives (Table 1) that have been evaluated for their biological activities as hypoxic selective derivatives (Table 1) that have been evaluated for their biological activities as hypoxic selective antianti-tumor agents derivatives possess varying substituents the 73 positions and 7 positions of the tumor agents
Summary
Quinoxaline 1,4-di-N-oxide derivatives have been the subject of worldwide interest in medicinal chemistry for a number of years due to their broad range of biological properties [1,2,3], as a variety of quinoxaline 1,4-dioxide derivatives have been reported to possess varying degrees of antibacterial [4,5], antimycobacterial [6], antitrypanocidal [7], antimalarial [8], anti-Chagas [9,10], antifungal [5,11], antioxidant/anti-inflammatory [12], and anticancer [13,14,15] activities. N-oxidation generally enhances the scope and level of their biological properties [1,2,16], and may be important for bioreduction [10]. It is Molecules 2017, 22, 1442; doi:10.3390/molecules22091442 www.mdpi.com/journal/molecules Molecules of 15. 22 of known that some quinoxaline 1,4-di-N-oxide derivatives undergo bioreduction under hypoxic well-known that some quinoxaline 1,4-di-N-oxide derivatives undergo bioreduction under hypoxic conditions, leading to the formation of a radical capable of cleaving DNA [2,3]. The latter may occur via direct abstraction of hydrogen atoms from DNA or production of DNA-cleaving hydroxyl via direct abstraction of hydrogen atoms from DNA or production of DNA-cleaving hydroxyl radicals, radicals, both mechanisms introducing oxidative stress within the target cells
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