Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A4 Mimetics (QNX-sLXms)

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure–activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

炎症消退障碍是诸多常见疾病的核心病理基础。近期研究证实，以脂氧素（lipoxins, LXs）为代表的脂质介质可介导炎症消退，提示其具备潜在治疗价值。本研究报道了一类新型含喹喔啉结构的合成脂氧素A4类似物（quinoxaline-containing synthetic-LXA4-mimetics, QNX-sLXms）的不对称合成方法。我们对8种新型化合物进行了炎症应答活性筛选。构效关系（Structure–activity relationship, SAR）研究显示，(R)-6（又名AT-02-CT）是本次测试中抗炎活性最强、效力最显著的化合物。(R)-6可显著抑制单核细胞与血管平滑肌细胞中脂多糖（lipopolysaccharide, LPS）及肿瘤坏死因子-α（tumor-necrosis-factor-α, TNF-α）诱导的核因子κB（NF-κB）活化。本研究进一步探究了(R)-6的分子靶点，发现其可激活内源性脂氧素受体甲酰肽受体2（formyl peptide receptor 2, ALX/FPR2）。我们进一步在急性炎症小鼠模型中开展了(R)-6的体内抗炎活性研究，结果与体外实验一致：(R)-6可在体内有效减轻炎症应答。上述结果证实，先导化合物QNX-sLXm (R)-6作为新型炎症调控剂，具备良好的潜在治疗应用价值。