摘要
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^(1)HNMR,^(13)CNMR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0.01mg/m L时对Hep G2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.
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^(1)H NMR,^(13)C 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]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]oxazin2-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.
作者
廖楚婕
阮洪瑶
姜峻峰
罗伦
胡扬根
Liao Chujie;Ruan Hongyao;Jiang Junfeng;Luo Lun;Hu Yanggen(School of Pharmaceutical Sciences,Hubei University of Medicine,Shiyan,Hubei 442000;Hubei Key Laboratory of Wudang Local Chinese Medicine Research,Hubei University of Medicine,Shiyan,Hubei 442000)
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2023年第2期763-770,共8页
Chinese Journal of Organic Chemistry
基金
国家自然科学基金(No.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(No.2022BMXKQY7)
湖北医药学院人才启动金资助计划(No.2018QDJZR13)
湖北医药学院大学生创新创业训练计划(Nos.202110929006,S202110929008和YSRTP202104)资助项目。