Zhou Tian-Yi, Guo Yang-Yang, Jing Qian-Qian, Wei Mei-Yan, Xu Wei-Feng, Gu Yu-Cheng, Shao Chang-Lun
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China; School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, People's Republic of China.
Eur J Med Chem. 2025 Jun 5;290:117541. doi: 10.1016/j.ejmech.2025.117541. Epub 2025 Mar 22.
Chronic inflammation is a trigger for many diseases that affect approximately 10-20 % of the population around the world. Herein, (±)-17-hydroxybrevianamide N (1) was isolated from the fungus Aspergillus sp. (CHNSCLM-0151) and exhibited strong inhibitory activity against nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 cell. A series of new derivatives (±)-3-(±)-29 was semisynthesized by structural modification of the imide, phenolic hydroxyl, and carbonyl groups from the natural product (±)-1. The results of anti-inflammatory activity demonstrated that (±)-4, (±)-6, (±)-9, (±)-22, (±)-23, and (±)-24 exhibited obviously NO inhibitory (P < 0.0001) in LPS-stimulated RAW264.7 cells. To further investigate the relationship between chirality and activity, the enantiomers of the above six compounds were obtained by chiral resolution. As expected, the bioactivity results indicated stereoselectivity in the anti-inflammatory effect among the different isomers. In particular, compound (+)-4S-23 inhibited NO concentration with an IC value of 0.5 μM, demonstrating 3-fold greater potency compared to its (R)-enantiomer, and achieving 40-fold superior potency over the positive control NG-monomethyl-l-arginine (L-NMMA). This compound demonstrated suppression of TNF-α (25.7 ± 1.5 %), IL-6 (54.5 ± 3.9 %) and IL-1β (92.9 ± 4.1 %) production at 2 μM. More importantly, mechanistic investigations revealed that (+)-4S-23 (0.2 μM) modulates the MAPK signaling pathway, specifically downregulating phosphorylation of p38, ERK, and JNK. Furthermore, (+)-4S-23 also exhibited potent inhibitory activity against the NF-κB pathway by suppressing the phosphorylation of IκB-α and blocking nuclear translocation of phosphorylated p65. Notably, these findings position (+)-4S-23 as a promising candidate for development as a novel anti-inflammatory therapeutic targeting both MAPK and NF-κB signaling nodes.
慢性炎症是引发许多疾病的诱因，这些疾病影响着全球约10%-20%的人口。在此，从曲霉属真菌（CHNSCLM-0151）中分离出（±）-17-羟基短柄酰胺N（1），其在脂多糖（LPS）诱导的RAW264.7细胞中对一氧化氮（NO）表现出强大的抑制活性。通过对天然产物（±）-1的酰亚胺、酚羟基和羰基进行结构修饰，半合成了一系列新的衍生物（±）-3-（±）-29。抗炎活性结果表明，（±）-4、（±）-6、（±）-9、（±）-22、（±）-23和（±）-24在LPS刺激的RAW264.7细胞中表现出明显的NO抑制作用（P<0.0001）。为了进一步研究手性与活性之间的关系，通过手性拆分获得了上述六种化合物的对映体。正如预期的那样，生物活性结果表明不同异构体在抗炎作用中具有立体选择性。特别是，化合物（+）-4S-23抑制NO浓度的IC值为0.5μM，其效力比其（R）-对映体高3倍，比阳性对照NG-单甲基-L-精氨酸（L-NMMA）高40倍。该化合物在2μM时表现出对TNF-α（25.7±1.5%）、IL-6（54.5±3.9%）和IL-1β（92.9±4.1%）产生的抑制作用。更重要的是，机制研究表明（+）-4S-23（0.2μM）调节MAPK信号通路，特别是下调p38、ERK和JNK的磷酸化。此外，（+）-4S-23还通过抑制IκB-α的磷酸化和阻断磷酸化p65的核转位，对NF-κB通路表现出强大的抑制活性。值得注意的是，这些发现使（+）-4S-23成为一种有前途的新型抗炎治疗候选药物，可靶向MAPK和NF-κB信号节点。
