Li Feng, Li Xiao-Min, Sheng Dekuan, Chen Shao-Ru, Nie Xin, Liu Zhuyun, Wang Decai, Zhao Qi, Wang Yitao, Wang Ying, Zhou Guo-Chun
School of Pharmaceutical Sciences, Nanjing Tech University Nanjing 211816 PR China
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Avenida da Universidade, Taipa Macao SAR PR China
RSC Adv. 2018 Mar 6;8(17):9440-9456. doi: 10.1039/c8ra01063c. eCollection 2018 Feb 28.
Antibacterials (which restore gut flora balance) and immunosuppressants (which correct immune defects) are two important and effective therapeutic agents for the treatment of inflammatory bowel disease (IBD) in clinical use today. Since the structural skeleton of andrographolide, isolated from , has become known as a natural antibiotic with anti-inflammation and heat-clearing and detoxifying properties, 14-aryloxy andrographolide derivatives have been designed, synthesized, and tested for their antibacterial effects on , , and , which are related to IBD. It has been discovered in this study that the andrographolide skeleton is more selective against , the 14-aryloxy group with basicity is important for antibacterial functions, and the 14-(8'-quinolinyloxy) group is a good pharmacophore with antibacterial activity. In addition, we found that 7b1 and 8b1 are good and selective inhibitors of ; two 14β-(8'-quinolinyloxy) andrographolide derivatives, 6b17 and 9b, exhibit good activity against , , and . Likewise and importantly, further exploration of immunosuppressant activity for IBD shows that compound 7b1 is a selective inhibitor of the TNF-α/NF-κB signaling pathway, whereas 8b1 is selectively active against the TLR4/NF-κB signaling pathway; moreover, the compounds 6b17 and 9b are active in inhibiting the IL-6/STAT3, TLR4/NF-κB, and TNF-α/NF-κB signaling pathways. Based on these results, we have further focused on the development of dual function inhibitors of IBD as antibacterial and immunosuppressant agents by structural modification of andrographolide.
抗菌剂（可恢复肠道菌群平衡）和免疫抑制剂（可纠正免疫缺陷）是当今临床上治疗炎症性肠病（IBD）的两种重要且有效的治疗药物。由于从穿心莲中分离出的穿心莲内酯的结构骨架已被认为是一种具有抗炎、清热和解毒特性的天然抗生素，因此设计、合成并测试了14-芳氧基穿心莲内酯衍生物对与IBD相关的大肠杆菌、金黄色葡萄球菌和白色念珠菌的抗菌作用。本研究发现，穿心莲内酯骨架对白色念珠菌具有更高的选择性，具有碱性的14-芳氧基基团对抗菌功能很重要，而14-（8'-喹啉氧基）基团是具有抗菌活性的良好药效基团。此外，我们发现7b1和8b1是白色念珠菌的良好且选择性抑制剂；两种14β-（8'-喹啉氧基）穿心莲内酯衍生物6b17和9b对大肠杆菌、金黄色葡萄球菌和白色念珠菌均表现出良好的活性。同样重要的是，对IBD免疫抑制活性的进一步探索表明，化合物7b1是TNF-α/NF-κB信号通路的选择性抑制剂，而8b1对TLR4/NF-κB信号通路具有选择性活性；此外，化合物6b17和9b在抑制IL-6/STAT3、TLR4/NF-κB和TNF-α/NF-κB信号通路方面具有活性。基于这些结果，我们通过对穿心莲内酯进行结构修饰，进一步专注于开发作为抗菌和免疫抑制剂的IBD双功能抑制剂。
