Aromatic lipoxin A4 and lipoxin B4 analogues display potent biological activities
Aromatic lipoxin A4 and lipoxin B4 analogues display potent biological activities
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DOI：
10.1021/jm060270d
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发表时间：
2007-11-29
影响因子：
7.3
通讯作者：
Guiry, Patrick J.
中科院分区：
文献类型：
--
作者：
O'Sullivan, Timothy P.;Vallin, Karl S. A.;Guiry, Patrick J.
脂氧素是一组具有生物活性的类二十烷酸，通常由跨细胞脂氧合酶活性形成。脂氧素A（4）（LXA（4））和脂氧素B-4（LXB 4）的生物合成已在多种炎性病症中检测到。天然脂氧素LXA（4）和LXB 4表现出有效的抑制和促分解生物作用。然而，它们的治疗潜力受到PG脱氢酶介导的氧化和还原的快速代谢失活的影响。本文报道了以Sharpless环氧化反应、Pd介导的Heck偶联反应和非对映选择性还原反应为关键反应，立体选择性合成芳香族LXA（4）和LXB 4类似物。随后的生物学测试表明，这些类似物显示出有效的生物活性。凋亡白细胞的吞噬清除在炎症消退中起关键作用。发现LXA（4）类似物（1 R）-3a和（1 S）-3a均刺激巨噬细胞对凋亡的多形核白细胞（PMN）的吞噬作用显著增加，其效力与天然LXA（4）的作用相当，尽管效力更强，而LXB 4类似物也刺激吞噬作用，在10（-11）M时观察到最大作用。LX刺激的吞噬作用与肌动蛋白细胞骨架的重排有关，与天然脂氧素的报道一致。使用酵母多糖诱导的腹膜炎作为急性炎症的小鼠模型（1 R）-3a显著降低了PMN积聚。
Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A(4) (LXA(4)) and Lipoxin B-4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native lipoxins LXA(4) and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA(4) and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA(4) analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA(4), albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10(-11) M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.