Petasis Nicos A, Keledjian Raquel, Sun Yee-Ping, Nagulapalli Kalyan C, Tjonahen Eric, Yang Rong, Serhan Charles N
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, USA.
Bioorg Med Chem Lett. 2008 Feb 15;18(4):1382-7. doi: 10.1016/j.bmcl.2008.01.013. Epub 2008 Jan 9.
A new class of chemically and metabolically stable lipoxin analogs featuring a replacement of the tetraene unit of native LXA(4) with a substituted benzo-fused ring system have been designed and studied. These molecules were readily synthesized via a convergent synthetic route involving iterative palladium-mediated cross-coupling, and exhibit enhanced chemical stability, as well as resistance to metabolic inactivation via eicosanoid oxido-reductase. These new LX analogs were evaluated in a model of acute inflammation and were shown to exhibit potent anti-inflammatory properties, significantly decreasing neutrophil infiltration in vivo. The most potent among these was compound 9 (o-[9,12]-benzo-15-epi-LXA(4) methyl ester. Taken together, these findings help identify a new class of stable and easily prepared LX analogs that may serve as novel tools and as promising leads for new anti-inflammatory agents with improved therapeutic profile.
设计并研究了一类新型的化学和代谢稳定的脂氧素类似物，其特征是用取代的苯并稠环系统取代天然LXA(4)的四烯单元。这些分子通过涉及迭代钯介导的交叉偶联的汇聚合成路线很容易合成，并表现出增强的化学稳定性，以及对类花生酸氧化还原酶介导的代谢失活的抗性。这些新的LX类似物在急性炎症模型中进行了评估，结果显示具有强大的抗炎特性，能显著减少体内中性粒细胞浸润。其中最有效的是化合物9（邻-[9,12]-苯并-15-表-LXA(4)甲酯）。综上所述，这些发现有助于确定一类新的稳定且易于制备的LX类似物，它们可能作为新型工具，并成为具有改善治疗特性的新型抗炎药物的有前景的先导化合物。
