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
| Autor: | Alexander M. Scherbakov, Pavel V. Dorovatovskii, Alexander А. Korlukov, Galina I. Buravchenko, Andrey E. Shchekotikhin |
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| Rok vydání: | 2020 |
| Předmět: |
Acetonitriles
Substituent Antineoplastic Agents Biochemistry Medicinal chemistry Cyclic N-Oxides 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Quinoxaline Quinoxalines Electronic effect Structural isomer Humans Cell Proliferation 030304 developmental biology Benzoxazoles 0303 health sciences Organic Chemistry Regioselectivity Biological activity Cell Hypoxia chemistry 030220 oncology & carcinogenesis MCF-7 Cells Polar effect Drug Screening Assays Antitumor Selectivity |
| Zdroj: | Current Organic Synthesis. 17:29-39 |
| ISSN: | 1570-1794 |
| DOI: | 10.2174/1570179416666191210100754 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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