New water-soluble hypoxia activated 7-aminoquinoxaline 1,4-dioxides, prepared by the regioselective Beirut reaction, acted as HIF-1α suppressors and induced apoptosis in hypoxic and MDR cancer cells.
A series of 3-aryl/hetarylquinoxaline-2-carbonitrile-1,4-dioxides was synthesized and evaluated against breast cancer cell lines in normoxia and hypoxia. Selected compounds in this series demonstrated better cytotoxicity and comparable hypoxia selectivity than tirapazamine. In contrast to Dox, quinoxaline-1,4-dioxides showed potent cytotoxicity against different MDR cells. Compound 2g inhibits of cancer cell growth through p53-independent mechanisms. Our results showed that compound 2g sensitized MCF-7 cells to metformin in hypoxia. Treatment with 2g results in the increase of ROS accumulation in cancer cells. Compound 2g can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents.
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.
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