Caffeic acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes.
Caffeic acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes.
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DOI：
10.1371/journal.pone.0031833
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Surette ME
中科院分区：
文献类型：
--
作者：
Boudreau LH;Maillet J;LeBlanc LM;Jean-François J;Touaibia M;Flamand N;Surette ME
5-脂氧合酶（5-LO）催化花生四烯酸（AA）转化为白三烯（LT），白三烯是炎症的重要脂质介质。LT直接参与炎症性疾病如哮喘、动脉粥样硬化和类风湿性关节炎;因此，抑制LT生物合成是治疗这些慢性疾病的策略。合成了咖啡酸的类似物，包括天然存在的咖啡酸苯乙酯（CAPE），并评价了其抑制人多形核白细胞（PMNL）和全血中5-LO和LT生物合成的能力。并测定了化合物的抗自由基和抗氧化活性。咖啡酸在浓度高达10 µM时不抑制5-LO活性或LT生物合成。CAPE抑制5-LO活性（IC 50 0.13 µM，95% CI 0.08-0.23 µM）的效果优于临床批准的5-LO抑制剂齐留通（IC 50 3.5 µM，95% CI 2.3-5.4 µM）。CAPE也比齐留通更有效地抑制PMNL中的LT生物合成，但化合物在全血中是等效的。CAPE的酰胺类似物的活性与齐留通相似。CAPE对LT生物合成的抑制是通过抑制5-LO和AA释放的结果。咖啡酸、CAPE及其酰胺类似物是自由基清除剂和抗氧化剂，IC 50值在低µM范围内;然而，CAPE的苯乙基部分是有效抑制5-LO和LT生物合成所必需的。CAPE是一种有效的LT生物合成抑制剂，可阻断5-LO活性和AA释放。CAPE结构可用作合理设计稳定且有效的LT生物合成抑制剂的框架。
5-lipoxygenase (5-LO) catalyses the transformation of arachidonic acid (AA) into leukotrienes (LTs), which are important lipid mediators of inflammation. LTs have been directly implicated in inflammatory diseases like asthma, atherosclerosis and rheumatoid arthritis; therefore inhibition of LT biosynthesis is a strategy for the treatment of these chronic diseases. Analogues of caffeic acid, including the naturally-occurring caffeic acid phenethyl ester (CAPE), were synthesized and evaluated for their capacity to inhibit 5-LO and LTs biosynthesis in human polymorphonuclear leukocytes (PMNL) and whole blood. Anti-free radical and anti-oxidant activities of the compounds were also measured. Caffeic acid did not inhibit 5-LO activity or LT biosynthesis at concentrations up to 10 µM. CAPE inhibited 5-LO activity (IC50 0.13 µM, 95% CI 0.08–0.23 µM) more effectively than the clinically-approved 5-LO inhibitor zileuton (IC50 3.5 µM, 95% CI 2.3–5.4 µM). CAPE was also more effective than zileuton for the inhibition of LT biosynthesis in PMNL but the compounds were equipotent in whole blood. The activity of the amide analogue of CAPE was similar to that of zileuton. Inhibition of LT biosynthesis by CAPE was the result of the inhibition of 5-LO and of AA release. Caffeic acid, CAPE and its amide analog were free radical scavengers and antioxidants with IC50 values in the low µM range; however, the phenethyl moiety of CAPE was required for effective inhibition of 5-LO and LT biosynthesis. CAPE is a potent LT biosynthesis inhibitor that blocks 5-LO activity and AA release. The CAPE structure can be used as a framework for the rational design of stable and potent inhibitors of LT biosynthesis.
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配体激活的人中性粒细胞中内源性腺苷对白三烯 B4 生物合成的抑制。
影响因子：
15.3
作者：
Krump, E;Picard, S;Mancini, J;Borgeat, P
通讯作者：
Borgeat, P
DOI：
10.1111/j.1742-1241.2007.01320.x
发表时间：
2007-04-01
影响因子：
2.6
作者：
Berger, W.;De Chandt, M. T. M.;Cairns, C. B.
通讯作者：
Cairns, C. B.
影响因子：
6.1
作者：
Liégeois, C;Lermusieau, G;Collin, S
通讯作者：
Collin, S
影响因子：
4.8
作者：
Flamand, N;Lefebvre, J;Borgeat, P
通讯作者：
Borgeat, P
影响因子：
3.6
作者：
Flamand, N;Surette, ME;Borgeat, P
通讯作者：
Borgeat, P