愈创木薁衍生物的设计合成及其抗氧化、抗炎活性研究

doi:10.6023/cjoc202204025

有机化学 ›› 2022, Vol. 42 ›› Issue (9): 2906-2913.DOI: 10.6023/cjoc202204025 上一篇下一篇

研究论文

愈创木薁衍生物的设计合成及其抗氧化、抗炎活性研究

李蕾^a^,^b, 朱聪聪^c^,^d, 朱全刚^c^,^d^,^*(), 陈中建^c^,^d^,^*(), 高希珂^b^,^*()

a 上海师范大学化学与材料科学学院上海 200234
b 中国科学院上海有机化学研究所中国科学院有机功能分子合成与组装化学重点实验室上海 200032
c 上海市皮肤病医院上海 200443
d 上海中药外用制剂创新工程技术研究中心上海 200443

收稿日期:2022-04-11 修回日期:2022-05-19 发布日期:2022-06-08
通讯作者: 朱全刚, 陈中建, 高希珂
基金资助:
国家自然科学基金(22075310); 上海市科学技术委员会(19XD1424700); 上海市科学技术委员会(20DZ2255200)

Design, Synthesis and Bioactivity Evaluation of Guaiazulene Derivatives with Antioxidant and Anti-inflammatory Activities

Lei Li^a^,^b, Congcong Zhu^c^,^d, Quangang Zhu^c^,^d(), Zhongjian Chen^c^,^d(), Xike Gao^b()

a College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234
b Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
c Shanghai Skin Disease Hospital, Shanghai 200443
d Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai 200443

Received:2022-04-11 Revised:2022-05-19 Published:2022-06-08
Contact: Quangang Zhu, Zhongjian Chen, Xike Gao
Supported by:
National Natural Science Foundation of China(22075310); Science and Technology Commission of Shanghai Municipality(19XD1424700); Science and Technology Commission of Shanghai Municipality(20DZ2255200)

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摘要/Abstract

动植物来源的愈创木薁(GA)具有抗菌、抗氧化、抗炎、抗过敏和低毒等特点, 其水溶性衍生物愈创木薁磺酸钠(GAS-Na)同样具有抗炎、促进上皮细胞生长和促进伤口愈合的作用. 然而, 商品化活性分子GA和GAS-Na对光、热等稳定性较差. 为了探索具有更高活性和稳定性的愈创木薁类生物功能分子, 合成了2,2'-二愈创木薁(BGA)和[2,2'-二愈创木薁]-1,1'-二磺酸钠(BGAS-Na), 并以GA和GAS-Na为对照, 评价了四个化合物的抗氧化能力, 研究了其对脂多糖(LPS)诱导小鼠巨噬细胞RAW 264.7的NO释放及细胞存活率的影响. 结果表明, BGA和BGAS-Na具有良好的抗氧化能力, 且稳定性较GA和GAS-Na有所提升; BGAS-Na在抗炎活性测试中具有最优的NO抑制率(IC₅₀值为5.64 μg/mL), 优于商品化分子GAS-Na, 且该抑制作用具有浓度依赖性. 此外, 四种化合物均不影响巨噬细胞的生长, 具有较低的细胞毒性. 因此, BGAS-Na有望成为具有发展潜力的抗炎药物.

关键词: 愈创木薁, 愈创木薁磺酸钠, 抗氧化, 抗炎, 细胞毒性, 巨噬细胞

Animal and plant-derived guaiazulene (GA) has the characteristics of antimicrobial, antioxidant, anti-inflammatory, anti-allergic and low toxicity. Sodium guaiazulene sulfonate (GAS-Na), a water-soluble derivative of GA, also has the effects of anti-inflammatory, promoting epithelial cell growth and wound healing. However, the commercial active molecules GA and GAS-Na have poor stability to light and heat. Therefore, in order to explore the guaiazulene biomedical functional molecules with higher activity and stability, 2,2'-biguaiazulene (BGA) and (2,2'-biguaiazulene)-1,1'-disulfonic acid sodium (BGAS-Na) were synthesized. Compared with GA and GAS-Na, the antioxidant activities of BGA and BGAS-Na were evaluated, and their biological effects on NO release and cell viability of LPS-induced RAW 264.7 macrophages were studied. The results showed that BGA and BGAS-Na had better antioxidant capacity and improved stability compared with GA and GAS-Na; BGAS-Na had the best NO inhibition rate in the anti-inflammatory activity test (the IC₅₀ value was 5.64 μg/ mL), which was better than that of the commercial molecule GAS-Na, and the inhibitory effect was dose-dependent. In addition, the four compounds did not affect the growth of macrophages and had low cytotoxicity. Therefore, BGAS-Na is expected to become a potential anti-inflammatory drug.

Key words: guaiazulene, sodium guaiazulene sulfonate, antioxidant, anti-inflammatory, cytotoxicity, macrophages

引用此文

李蕾, 朱聪聪, 朱全刚, 陈中建, 高希珂. 愈创木薁衍生物的设计合成及其抗氧化、抗炎活性研究[J]. 有机化学, 2022, 42(9): 2906-2913.

Lei Li, Congcong Zhu, Quangang Zhu, Zhongjian Chen, Xike Gao. Design, Synthesis and Bioactivity Evaluation of Guaiazulene Derivatives with Antioxidant and Anti-inflammatory Activities[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2906-2913.

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图/表 7

图1. 薁、愈创木薁和愈创木薁磺酸钠的结构式

Figure 1. Chemical structures of azulene, guaiazulene and sodium guaiazulene sulfonate

图式1. GAS-Na, BGA和BGAS-Na的合成路线

Scheme 1. Synthesis routes of GAS-Na, BGA and BGAS-Na

Compd.	X	Yield/%
Compd.	X	Step A^a		Step B^b		Total yield^c
2a	Br	85	98		83
2b	I	53	86		46

表1. 愈创木薁卤代物2a和2b在Step A和Step B中的收率和转化率

Table 1. Yields and the conversion of 2a and 2b in step A and step B

图2. FRAP法测定化合物的相对抗氧化能力

Figure 2. Determination of antioxidant capacity of compounds by FRAP method Data are given as mean±SEM. Statistical analysis is performed by one- way analysis of variance (ANOVA). **P<0.01

图3. 化合物在不同作用时间下对DPPH自由基的清除率

Figure 3. Scavenging rate of compounds on DPPH free radicals at different action times Data are given as mean±SEM. Statistical analysis is performed by Two-way analysis of variance (ANOVA). **P<0.01, ****P<0.0001

图4. 化合物对LPS激活的RAW 264.7细胞产生NO的影响

Figure 4. Effects of compounds on NO production in LPS-activated RAW 264.7 Cells Data are given as mean ± SEM. Figure 4a-4d show the substances added in different experimental groups. All concentration units are μg/mL. Figure 4e shows the inhibition rate of the compounds on the production of NO at different concentrations * indicates significant difference (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001)

图5. 化合物对巨噬细胞RAW 264.7细胞存活率的影响

Figure 5. Effects of compounds on the cell viability of macrophage RAW 264.7 cells Data are given as mean±SEM

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愈创木薁衍生物的设计合成及其抗氧化、抗炎活性研究

Design, Synthesis and Bioactivity Evaluation of Guaiazulene Derivatives with Antioxidant and Anti-inflammatory Activities

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