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.
Material and Method:
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.
A series of Mn(i) photo-activated carbon monoxide-releasing molecules with benzimidazole coligands: synthesis, structural characterization, CO releasing properties and biological activity evaluation