State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, PR China.
Eur J Med Chem. 2012 Apr;50:63-74. doi: 10.1016/j.ejmech.2012.01.036. Epub 2012 Jan 28.
Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.
盐酸青藤碱（1）临床上可用于治疗类风湿性关节炎（RA），但其疗效相当弱。在本研究中，设计并合成了通过可变长度接头的新型盐酸青藤碱同源二聚体和单体库，并通过 RAW264.7 细胞和小鼠评估了它们的生物活性。在这些化合物中，化合物 2f 和 3b 对一氧化氮（NO）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的产生具有更强的抑制作用，优于 1。初步的机制研究表明，3b 特异性抑制核因子-κB（NF-κB）信号通路，2f 同时抑制 NF-κB 和丝裂原活化蛋白激酶（MAPK）级联。此外，3b 和 2f 显著减轻了脂多糖（LPS）诱导的死亡率。这两种化合物可能是抗炎药物发现的有价值的候选物。
