Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs.
Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs.
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DOI：
10.1016/j.plefa.2009.09.004
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Serhan CN
中科院分区：
文献类型：
--
作者：
Sun YP;Tjonahen E;Keledjian R;Zhu M;Yang R;Recchiuti A;Pillai PS;Petasis NA;Serhan CN
脂氧素(LXs)是一种有效的内源性反调节脂质介质，可抑制急性炎症并促进其消退。在这里，我们介绍了我们对一类新的热稳定性和代谢稳定性的苯并-LXA4类似物的研究，这些类似物具有有效的抗炎作用，更容易合成。用苯并稠环体系取代天然LXA4的四烯单元，不仅提高了热稳定性，而且使这些类似物的合成高度收敛和高效。此外，它们还能抵抗二十烷基类氧化还原酶的快速催化和失活。与天然LXs一样，o-[9，12]-苯并-ω6-表-LXA4、o-[9，12]-苯并-脱氧-LXA4、m-[9，12]-苯并-ω6-表-LXA4和[9，14]-苯并-ω6-(R/S)-LXA4在纳克剂量下对小鼠腹膜炎中性粒细胞浸润和促炎细胞因子的产生具有明显的时间依赖性抑制作用，对后肢肺缺血再灌注损伤具有器官保护作用。O-[9，12]-苯并-ω6-表-LXA4和m-[9，12]-苯并-ω6-表-LXA4在纳克剂量下效果最好，均可减少中性粒细胞的渗透约32%，而o-[9，12]-苯并脱氧-LXA4和[9，15]-ω6-(R/S)-LXA4的效果较差。[9，12]-苯并-ω6-表位-LXA4还激活了脂氧素A4GPCR，并增加了巨噬细胞的吞噬活性。综上所述，这些发现展示了新一代LXA4稳定的类似物，它们易于合成和抗炎。这些苯并-LXA4类似物有望成为新的治疗方法以及评估内源性抗炎和消退机制的工具。
Lipoxins (LXs) are potent endogenous counter-regulatory lipid mediators that dampen acute inflammation and promote its resolution. Here, we present our investigation of a new class of thermally and metabolically stable benzo-LXA4 analogs that are potently anti-inflammatory and easier to synthesize. Replacement of the tetraene unit of native LXA4 with a benzo-fused ring system not only increases the thermal stability but also enables highly convergent and efficient syntheses of these analogs. In addition, they resist rapid catalysis and inactivation by eicosanoid oxidoreductase. Like native LXs, o-[9, 12]-benzo-ω6-epi-LXA4, o-[9, 12]-benzo-deoxy-LXA4, m-[9, 12]-benzo-ω6-epi-LXA4 and [9, 14]-benzo-ω6-(R/S)-LXA4 demonstrated potent time-dependent reduction, at nanogram dosages, of PMN infiltration and pro-inflammatory cytokine generation in vivo in murine peritonitis and were organ protective in hind limb ischemia-reperfusion injury of the lung. The o-[9, 12]-benzo-ω6-epi-LXA4 and m-[9, 12]-benzo-ω6-epi-LXA4 were most potent in nanogram doses; both decreased PMN infiltration by ~32%, while o-[9, 12]-benzo-deoxy-LXA4 and [9, 15]-ω6-(R/S)-LXA4 were less potent. The [9,12]- benzo-ω6-epi-LXA4 also activated a lipoxin A4 GPCR and increased macrophage phagocytic activity. Taken together, these findings demonstrate a new generation of LXA4 stable analogs that are easy to synthesize and anti-inflammatory. These benzo-LXA4 analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution.
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影响因子：
82.9
作者：
Levy, BD;DeSanctis, GT;Serhan, CN
通讯作者：
Serhan, CN
影响因子：
1.8
作者：
Nokami, J;Furukawa, A;Kurozumi, S
通讯作者：
Kurozumi, S
影响因子：
7.3
作者：
O'Sullivan, Timothy P.;Vallin, Karl S. A.;Guiry, Patrick J.
通讯作者：
Guiry, Patrick J.
影响因子：
7.3
作者：
Bannenberg, G;Moussignac, RL;Serhan, CN
通讯作者：
Serhan, CN
影响因子：
4.4
作者：
Bannenberg, GL;Chiang, N;Serhan, CN
通讯作者：
Serhan, CN