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Background: Quinoxaline 1,4-dioxides have a broad range of biological activity that causes a growing interest in their derivatives for drug discovery. Recent studies demonstrated that quinoxaline 1,4- dioxides have a promising anticancer activity and good hypoxia-selectivity., Objective: The preparation, isolation, structure characterization, and screening for anticancer activity of the first representatives of 6-substituted quinoxaline-2-carbonitrile 1,4-dioxides have been described., Materials and Methods: A series of 7- and 6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides was synthesized by the Beirut reaction. The cytotoxicity was assessed by MTT test (72 h incubation) in normoxia (21% O2) and hypoxia (1% O2) conditions., Results: We found that during the Beirut reaction between a benzofuroxan bearing an electron withdrawing group and benzoylacetonitrile in the presence of triethylamine, in addition to well-known 7-substituted quinoxaline-2-carbonitrile 1,4-dioxides 7-11a, the 6-isomers 7-11b are formed. Moreover, the yield of the 6- isomers increased with the increase in the electron-withdrawing character of the substituent. For benzofuroxans with CO2Me and CF3 groups, 6-substituted quinoxaline-2-carbonitrile 1,4-dioxides 10-11b were the major products. Despite similarities in physicochemical and spectroscopic properties, the obtained isomers exhibit considerable differences in their anticancer activity and hypoxia selectivity., Conclusion: Substituents and their electronic effects play a key role in the formation of 7- and 6-substituted quinoxaline-2-carbonitrile 1,4-dioxides in the Beirut reaction and in the cytotoxicity properties of the obtained isomers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)