Journal
CHINESE JOURNAL OF ORGANIC CHEMISTRY
Volume 43, Issue 2, Pages 763-770Publisher
SCIENCE PRESS
DOI: 10.6023/cjoc202206048
Keywords
benzo[e][1,3]oxazin-4-ol; synthesis; aza-Wittig reaction; antitumor; antioxidant
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In this study, 3-aryl-2-imino-benzo[e][1,3]-oxazin-4-ol derivatives were efficiently synthesized by aza-Wittig tandem reaction. Their structures were confirmed by NMR and HRMS, and the most active compound showed potential antitumor activities against HepG2 and HeLa cell lines. The compounds also exhibited antioxidant properties.
Benzoxazines are important heterocycles bearing remarkable biological activities, which widely used in medicine, pesticide and other fields. In this study, 3-aryl-2-imino-benzo[e][1,3]-oxazin-4-ol derivatives 4a similar to 4k were efficiently synthesized by aza-Wittig tandem reaction with simple and easy materials under mild conditions, and their structures were confirmed by H-1 NMR, C-13 NMR and HRMS. X-Ray structure analysis of diethyl (Z)-2-((4-hydroxy-3-phenyl-3,4-dihydro-2H-benzo[e]-[1,3]oxazin-2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4a) verified that the carbon-nitrogen (C = N) assigned Z-configuration to the compound structure. In vitro, the antitumor activities of compounds 4a similar to 4k were analyzed with CCK8 standard method. The results indicated that most of the compounds showed potential antitumor activities. Among them, the inhibitory rate of the most active compound diethyl (Z)-2-((4-hydroxy-6-methyl-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-ylidene)amino)-5-methyl-furan-3,4-dicarboxylate (4e) against HepG2 and HeLa cell lines at the concentration of 0.01 mg/mL were 45.83% and 42.76%, respectively, which were weaker than the commercial gefitinib. Furthermore, their antioxidant properties were detected via 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay. The results showed that the IC50 values of free radical scavenging rates of diethyl (Z)-2-((4-hydroxy-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4d), 4e and diethyl (Z)-2-((6,8-dichloro-4-hydroxy-3-phenyl-3,4-dihydro2H-benzo[e][1,3]oxazin-2-ylidene)amino)-5-methylfuran-3,4-dicarboxylate (4j) were 0.294, 0.255 and 0.338 mmol/L, respectively, which slightly higher than that of the control ascorbic acid.
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