奥沙普秦丹皮酚酯的合成及抗炎活性研究

doi:10.6023/cjoc201903020

有机化学 ›› 2019, Vol. 39 ›› Issue (10): 2958-2964.DOI: 10.6023/cjoc201903020 上一篇下一篇

研究简报

奥沙普秦丹皮酚酯的合成及抗炎活性研究

徐学涛^a, 陈洁^a, 林芷晴^a, 李冬利^a, 张焜^a, 盛钊君^a^*(), 王少华^a^b^c^*(), 朱顺^c, Abdullah M. Asiri^d

a 五邑大学生物科技与大健康学院广东江门 529020
b 兰州大学药学院兰州 730000
c 扬子江药业集团江苏紫龙药业有限公司江苏常州 213100

收稿日期:2019-03-12 修回日期:2019-05-15 发布日期:2019-05-21
通讯作者: 盛钊君,王少华 E-mail:wyuchemszj@126.com;wangshh@lzu.edu.cn
基金资助:
广东省教育厅基金(2017KTSCX185);广东省教育厅基金(2017KSYS010);广东省教育厅基金(2016KCXTD005);五邑大学青年团队项目(2016td01);国家自然科学基金(Nos. 21472077);国家自然科学基金(21772071)

Synthesis and Anti-inflammatory Effects of Oxaprozin-Paeonol Ester

Xu, Xuetao^a, Chen, Jie^a, Lin, Zhiqing^a, Li, Dongli^a, Zhang, Kun^a, Sheng, Zhaojun^a^*(), Wang, Shaohua^a^b^c^*(), Zhu, Shun^c, Abdullah M. Asiri^d

a School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, Guangdong, China
b School of Pharmacy, Lanzhou University, Lanzhou 730000, China
c Yangtze River Pharmaceutical Group Jiangsu Zilong Pharmaceutical Co., Ltd., Changzhou 213100, Jiangsu, China

Received:2019-03-12 Revised:2019-05-15 Published:2019-05-21
Contact: Sheng, Zhaojun,Wang, Shaohua E-mail:wyuchemszj@126.com;wangshh@lzu.edu.cn
Supported by:
Project supported by the Department of Education of Guangdong Province(2017KTSCX185);Project supported by the Department of Education of Guangdong Province(2017KSYS010);Project supported by the Department of Education of Guangdong Province(2016KCXTD005);the Youth Team Fund of Wuyi University(2016td01);the National Natural Science Foundation of China(Nos. 21472077);the National Natural Science Foundation of China(21772071)

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摘要/Abstract

奥沙普秦是临床常用抗炎药物, 口服易造成胃肠穿孔, 与其分子结构中羧酸基团引起的局部刺激密切相关. 丹皮酚是牡丹的有效成分, 有抗炎、抗氧化的功效. 合成了奥沙普秦丹皮酚酯(OPE), 试图在避免胃肠道并发症的同时, 提高其抗炎效果. 通过12-O-十四烷基佛波醇-13-乙酸酯(TPA)诱导的小鼠耳水肿模型评价了OPE的局部抗炎作用. 结果显示局部应用OPE可有效改善TPA诱导的耳廓肿胀, 抗炎效果是奥沙普秦的2倍, 是丹皮酚的4倍. 而且OPE可有效改善耳片组织IL-1β, IL-6和TNF-α的表达, 效果优于奥沙普秦和丹皮酚. 进一步研究显示OPE可通过阻断IκB激酶(IKK)活性来下调kappa-κB (NF-κB)的活性.

关键词: 奥沙普秦, 丹皮酚, 炎症, 耳廓肿胀模型

Oxaprozin is a common anti-inflammatory drug in the clinic. Oral medication of oxaprozin potentially induces the GI perforation, which is caused by the local irritation of its carboxylic acid group. Paeonol is an active ingredient of peony, and has anti-inflammatory and anti-oxidant effects. So oxaprozin-paeonol ester (OPE) was designed to avoid the GI complications and enhence corresponding anti-inflammatory. The topical anti-inflammatory effects of OPE was evaluated in a 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema model. The results showed that topical treatment of OPE could effectively improve the TPA-induced ear edema and its anti-inflammatory effect is 2 times higher than that of oxaprozin and 4 times than that of paeonol. Moreover, OPE treatment could effectively mitigate the expression of IL-1β, IL-6, and TNF-α, and its effect is better than that of oxaprozin or paeonol. Furthor study demonstrated that topical treatment of OPE could obviously down-regulate the activation of factor kappa-κB (NF-κB) by blocking IκB kinase (IKK) activities. Accordingly, OPE might be used as a promising anti-inflammatory agent for inflammation-associated skin diseases.

Key words: Oxaprozin, Paeonol, Inflammatory, Ear edema mode

引用此文

徐学涛, 陈洁, 林芷晴, 李冬利, 张焜, 盛钊君, 王少华, 朱顺, Abdullah M. Asiri. 奥沙普秦丹皮酚酯的合成及抗炎活性研究[J]. 有机化学, 2019, 39(10): 2958-2964.

Xu, Xuetao, Chen, Jie, Lin, Zhiqing, Li, Dongli, Zhang, Kun, Sheng, Zhaojun, Wang, Shaohua, Zhu, Shun, Abdullah M. Asiri. Synthesis and Anti-inflammatory Effects of Oxaprozin-Paeonol Ester[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2958-2964.

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图/表 9

Figure 1. Chemical structure of oxaprozin and paeonol

Scheme 1. Synthesis of OPE

Figure 2. Effect of oxaprozin, paeonol, OPE on TPA-induced ear edema Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05

Figure 3. Effect of oxaprozin, paeonol, OPE on TPA-induced histological changes of ear edema (H&E staining) Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05. Magnification 200×

Figure 4. Effect of oxaprozin, paeonol, OPE on TPA-induced TNF-α, IL-1β, and IL-6 Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05. Magnification 200×

Figure 5. Effect of oxaprozin, paeonol, OPE on TPA-induced NF-κB activation Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05. Magnification 200×

Figure 6. Effect of oxaprozin, paeonol, OPE on TPA-induced IKK Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05. Magnification 200×

Figure 7. Effect of oxaprozin, paeonol, OPE on TPA-induced Akt Data are presented as mean±SE (n=4). Compared to TPA alone, *P<0.05. Magnification 200×

Figure 8. A model of OPE modulation of TPA-induced signal transduction pathways in mouse skin in vivo

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奥沙普秦丹皮酚酯的合成及抗炎活性研究

Synthesis and Anti-inflammatory Effects of Oxaprozin-Paeonol Ester

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