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

doi:10.6023/cjoc202204025

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (9): 2906-2913.DOI: 10.6023/cjoc202204025 Previous Articles Next Articles

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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

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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Abstract

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

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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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Fig. & Tab. 7

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

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

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

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

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

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)

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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References 23

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