3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物的合成及活性评价
收稿日期: 2022-07-27
修回日期: 2022-08-23
网络出版日期: 2022-10-10
基金资助
国家自然科学基金(81773746); 湖北医药学院“十四五”省级优势特色学科群(生物与医药)2022年(2022BMXKQY7); 湖北医药学院人才启动金资助计划(2018QDJZR13); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(202110929006); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(S202110929008); 湖北医药学院大学生创新创业训练计划(Nos. 202110929006, S202110929008和YSRTP202104(YSRTP202104)
Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives
Received date: 2022-07-27
Revised date: 2022-08-23
Online published: 2022-10-10
Supported by
National Natural Science Foundation of China(81773746); Advantages Discipline Group (Biology and Medicine) Project in Higher Education of Hubei Province (2021-2025(2022BMXKQY7); Cultivating Project for Young Scholar at Hubei University of Medicine(2018QDJZR13); Innovative Research Program for College Students of Hubei University of Medicine(202110929006); Innovative Research Program for College Students of Hubei University of Medicine(S202110929008); Innovative Research Program for College Students of Hubei University of Medicine(YSRTP202104)
苯并噁嗪是一类重要的稠合杂环, 其衍生物具有不同的生物活性而被广泛地应用于医药、农药等领域. 本研究在温和的条件下, 以简单易得的原料, 应用aza-wittig反应高效地合成了3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物4a~4k, 其结构通过1H NMR, 13C NMR和高分辨质谱确认. 通过单晶X射线衍射对3-苯基-2-(3,4-二乙氧基羰基-5-甲基-呋喃-2-亚胺)-苯并[1,3]噁嗪-4-醇(4a)进行了结构分析, 确认了化合物结构中碳氮双健(C=N)为Z式构型. 运用CCK8方法对目标化合物4a~4k进行了体外抗肿瘤活性评价, 其中3-(4-氟-苯亚胺-2-(3,4-二乙氧基羰基-5-甲基-呋喃- 2-亚胺)-6-氯-苯并[1,3]噁嗪-4-醇(4e)在浓度为0.01 mg/mL时对HepG2和Hela两种细胞系的抑制率分别为45.83%和42.76%, 略低于对照药物吉非替尼(68.56%和79.76%), 表现出潜在的抗肿瘤活性. 通过1,1-二苯基-2-三硝基苯肼(DPPH)自由基裂解法测试了目标化合物的抗氧化性, 结果显示3-苯基-2-(3,4-二乙氧基羰基-5-甲基-呋喃-2-亚胺)-6-硝基-苯并[1,3]噁嗪-4-醇(4d)、4e和3-苯基-2-(3,4-二乙氧基羰基-5-甲基-呋喃-2-亚胺)-6,8-二氯-苯并[1,3]噁嗪-4-醇(4j)的自由基的清除率IC50值分别为0.294、0.255和0.338 mmol/L, 与对照抗坏血酸的IC50值稍大.
关键词： 苯并[e]-1,3-噁嗪-4-醇; 合成; aza-Wittig反应; 抗肿瘤; 抗氧化性
廖楚婕 , 阮洪瑶 , 姜峻峰 , 罗伦 , 胡扬根 . 3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物的合成及活性评价[J]. 有机化学, 2023 , 43(2) : 763 -770 . DOI: 10.6023/cjoc202206048
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~4k were efficiently synthesized by aza-Wittig tandem reaction with simple and easy materials under mild conditions, and their structures were confirmed by 1H NMR, 13C 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~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]oxa- zin-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-dihydro- 2H-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.
Key words： benzo[e][1,3]oxazin-4-ol; synthesis; aza-Wittig reaction; antitumor; antioxidant
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