DESIGN OF LIPOXIN A(4) STABLE ANALOGS THAT BLOCK TRANSMIGRATION AND ADHESION OF HUMAN NEUTROPHILS
DESIGN OF LIPOXIN A(4) STABLE ANALOGS THAT BLOCK TRANSMIGRATION AND ADHESION OF HUMAN NEUTROPHILS
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DOI：
10.1021/bi00044a041
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发表时间：
1995-11-07
期刊：
影响因子：
2.9
通讯作者：
MADARA, JL
中科院分区：
文献类型：
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作者：
SERHAN, CN;MADDOX, JF;MADARA, JL
脂氧素（LX）是具有生物活性的类二十烷酸，其携带四烯结构并且部分地通过抑制中性粒细胞迁移和粘附而充当炎症调节剂。脂氧素A（4）通过局部代谢转化为无活性的LX代谢物而快速调节，其中脱氢是主要途径。在此，设计了几种LXA（4）类似物，它们抵抗分化的HL-60细胞和重组15-羟基前列腺素脱氢酶的快速转化，在这些系统中，天然LXA（4）在几分钟内被降解。重组脱氢酶的转化率顺序为LXA（4）甲酯> PGE（2）近似于PGE（2）甲酯> LXA（4）>新型LXA（4）类似物。此外，15（R/S）-甲基-LXA（4）、15-环己基-LXA（A）和16-苯氧基-LXA（4）被证明保留了LXA（4）的生物活性，并抑制中性粒细胞穿过极化上皮细胞单层的迁移以及与血管内皮细胞的粘附。这些结果表明，可以使用这些标准来设计LXA（4）类似物，以抵抗快速转化并保留天然LXA（4）的生物学作用。此外，结果表明，LXA（4）稳定类似物可以在体外和体内都是有用的工具，以评估LXA（4）的作用和治疗潜力。
Lipoxins (LX) are bioactive eicosanoids that carry a tetraene structure and serve as regulators of inflammation, in part by inhibiting neutrophil migration and adhesion. Lipoxin A(4) is rapidly regulated by conversion to inactive LX metabolites via local metabolism that involves dehydrogenation as the predominant route. Here, several LXA(4) analogs were designed that resisted rapid conversion by both differentiated HL-60 cells and recombinant 15-hydroxyprostaglandin dehydrogenase, systems where native LXA(4) is degraded within minutes. The rank order of conversion by recombinant dehydrogenase was LXA(4) methyl ester > PGE(2) approximate to PGE(2) methyl ester > LXA(4) >>> the novel LXA(4) analogs. In addition, 15(R/S)-methyl-LXA(4), 15-cyclohexyl-LXA(A), and 16-phenoxy-LXA(4) proved to retain LXA(4) bioactivity and inhibited neutrophil transmigration across polarized epithelial cell monolayers as well as adhesion to vascular endothelial cells. These results indicate that LXA(4) analogs can be designed using these criteria to resist rapid transformation and to retain biological actions of native LXA(4). Moreover, the results suggest that LXA(4) stable analogs can be useful tools both in vitro and in vivo to evaluate LXA(4) actions and therapeutic potential.