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Revision of the Regioselectivity of the Beirut Reaction of Monosubstituted Benzofuroxans with Benzoylacetonitrile. 6-Substituted quinoxaline-2-carbonitrile 1,4- dioxides: Structural Characterization and Estimation of Anticancer Activity and Hypoxia Selectivity

[ Vol. 17 , Issue. 1 ]

Author(s):

Galina I. Buravchenko, Alexander M. Scherbakov, Alexander А. Korlukov, Pavel V. Dorovatovskii and Andrey E. Shchekotikhin*   Pages 29 - 39 ( 11 )

Abstract:


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.

Keywords:

6(7)-substituted-3-phenylquinoxaline-2-carbonitrile 1, 4-dioxides, structural isomers, CIGAR-HMBC method, X-ray structural analysis, antiproliferative activity, hypoxia-selective cytotoxins, Beirut reaction.

Affiliation:

Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Blokhin National Medical Research Center of Oncology, 24 Kashirskoye sh., Moscow 115522, Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St., Moscow 119991, National Research Center “Kurchatov Institute”, 1 Akademika Kurchatova pl., Moscow 123182, Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021

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