Xiao Yan, Chang Ye, Liu Yu-Yan, Li Ting-Ting, Qu Wen-Rong, Yuan Cheng, Chen Lin, Huang Shuai, Zhou Xian-Li
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, PR China.
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, PR China; School of School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, PR China.
Bioorg Chem. 2024 Dec;153:107834. doi: 10.1016/j.bioorg.2024.107834. Epub 2024 Sep 21.
In this study, four franchetine-type diterpenoid alkaloids (1-4) were isolated from Aconitum sinoaxillare, and fourteen diverse franchetine analogs (5-18) were synthesized. Compounds 1, 2, 7 and 16 exhibited stronger inhibitory effects on NO production when compared to celecoxib. Among them, compound 1 had the best inhibitory effect on iNOS and COX-2 inflammatory proteins. The in vitro studies displayed that the anti-inflammatory effect of the most active compound 1 was ascribed to the inhibition of the TLR4-MyD88/NF-κB/MAPKs signalling pathway. Consequently, this led to a inhibition in the expression of inflammatory factors or mediators including NO, ROS, TNF-α, IL-6, IL-1β, iNOS, and COX-2. Additionally, compound 1 had low toxicity (LD > 20 mg/kg) in mice, and it had notable analgesic effects on acetic acid-induced visceral pain (ED = 2.15 ± 0.07 mg/kg). Moreover, compound 1 exhibited a distinct reduction in the Na1.7 and Na1.8 channel currents during both resting and half-inactivated states at 50 μM. The present study enriches the pharmacological activities of franchetine derivatives and provides valuable insights for the development of novel anti-inflammatory and analgesic agents.
在本研究中，从中华腋花乌头中分离出四种川鄂乌碱型二萜生物碱（1-4），并合成了十四种不同的川鄂乌碱类似物（5-18）。与塞来昔布相比，化合物1、2、7和16对一氧化氮（NO）生成表现出更强的抑制作用。其中，化合物1对诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）炎症蛋白具有最佳抑制作用。体外研究表明，活性最强的化合物1的抗炎作用归因于对Toll样受体4（TLR4）-髓样分化因子88（MyD88）/核因子κB（NF-κB）/丝裂原活化蛋白激酶（MAPKs）信号通路的抑制。因此，这导致包括NO､活性氧（ROS）､肿瘤坏死因子-α（TNF-α）､白细胞介素-6（IL-6）､白细胞介素-1β（IL-1β）､iNOS和COX-2在内的炎症因子或介质的表达受到抑制。此外，化合物1在小鼠中具有低毒性（半数致死量>20mg/kg），并且对醋酸诱导的内脏疼痛具有显著的镇痛作用（半数有效量=2.15±0.07mg/kg）。此外，在50μM时，化合物1在静息和半失活状态下均使钠通道1.7（Na1.7）和钠通道1.8（Na1.8）电流明显降低。本研究丰富了川鄂乌碱衍生物的药理活性，并为新型抗炎和镇痛药物的开发提供了有价值的见解。
