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

doi:10.6023/cjoc202206048

有机化学 ›› 2023, Vol. 43 ›› Issue (2): 763-770.DOI: 10.6023/cjoc202206048 上一篇下一篇

研究简报

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

廖楚婕^a^,^b, 阮洪瑶^a^,^b, 姜峻峰^a^,^b, 罗伦^a^,^b^,^*(), 胡扬根^a^,^b^,^*()

a 湖北医药学院药学院湖北十堰 442000
b 湖北医药学院武当特色中药研究湖北省重点实验室湖北十堰 442000

收稿日期:2022-07-27 修回日期:2022-08-23 发布日期: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

Chujie Liao^a^,^b, Hongyao Ruan^a^,^b, Junfeng Jiang^a^,^b, Lun Luo^a^,^b(), Yanggen Hu^a^,^b()

a School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000
b Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei 442000

Received:2022-07-27 Revised:2022-08-23 Published:2022-10-10
Contact: *E-mail: luolun@hbmu.edu.cn;huyg@hbmu.edu.cn
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)

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摘要/Abstract

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

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 by¹H 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

引用此文

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.

Chujie Liao, Hongyao Ruan, Junfeng Jiang, Lun Luo, Yanggen Hu. Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 763-770.

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图/表 7

图式1. 3-芳基-2-亚胺苯并[e]-1,3-噁嗪-4-醇衍生物4a~4k的合成路线

Scheme 1. Synthetic route of 3-aryl-2-imino-benzo[e][1,3]-oxazin-4-ol derivatives 4a~4k

图式2. 化合物4的形成

Scheme 2. Formation of compound 4

图1. 化合物4a的晶体结构和分子间O-H…O氢键堆积图

Figure 1. Crystal structure and intermolecular O-H…O hydrogen bonding packing diagram of the compound 4a

图2. 化合物4b和4'b的结构优化及能量

Figure 2. Optimized structures and energy of compounds 4b and 4'b

Compd.	IC₅₀/(mmol•L^-1)	Compd.	IC₅₀/(mmol•L^-1)
4a	1.958	4g	6.629
4b	5.078	4h	0.764
4c	0.842	4i	9.534
4d	0.294	4j	0.338
4e	0.255	4k	1.226
4f	2.555	Ascorbic acid (cont.)	96.32%^a0.103 (lit.^[21])^b

表1. 3-芳基-2-亚胺-苯并[e]-1,3-噁嗪-4-醇衍生物4a~4k的抗氧化活性(30 min)

Table 1. Anti-oxidant activity (30 min) of 3-aryl-2-iminobenzo- [e][1,3]-oxazin-4-ol derivatives 4a~4k

图3. 浓度均为0.2 mg/mL时化合物4d、4e、4h和4k自由基的清除率随时间的变化

Figure 3. Variation with time of free radical scavenging rate of compounds 4d, 4e, 4h and 4k when the concentration was 0.2 mg/mL, respectively

Compd.	Inhibitory rate^a/%
Compd.	Hela	HepG2
4a	6.84	-9.64
4b	19.55	-4.00
4c	12.37	7.54
4d	11.77	-4.77
4e	45.83	42.76
4f	16.21	0.40
4g	24.10	5.28
4h	31.43	26.27
4i	42.54	23.48
4j	41.85	5.53
4k	35.73	17.90
Gifitinib	79.76	68.56

表2. 3-芳基-2-亚胺苯并[e]-1,3-噁嗪-4-醇衍生物4a~4k的抗肿瘤活性

Table 2. Antitumor activity of 3-aryl-2-imino-benzo[e][1,3]- oxazin-4-ol derivatives 4a~4k

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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

Synthesis and Activity Evaluation of 3-Aryl-2-imino-benzo[e][1,3]-oxazin-4-ol Derivatives

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