A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway

作者：Tu, Tingyue; Yu, Mao; Zhang, Yanping; Shi, Xiafei; Xu, Jinhao; Hu, Junqing; Gan, Jingjing; He, Wei; Dong, Lei; Han, Jianlin^*; Huang, Zhen^*; Pan, Yi; Zhang, Junfeng

来源：Biochemical Pharmacology, 2018, 155: 275-287.

DOI：10.1016/j.bcp.2018.07.020

• Fluorinated triazole derivatives
• Twist1
• Macrophage
• Colitis

Hyperactivated macrophages play a key role in the initiation and perpetuation of mucosal inflammation in Crohn's disease (CD). Increasing evidence suggests that the basic helix-loop-helix (bHLH) repressor Twist1 can suppress activation of nuclear factor-kappa B (NF-kappa B) and the subsequent production of TNF-alpha, which are both essential elements of macrophage activation. Thus, developing novel therapeutic strategies to enhance Twist1 expression and to inhibit macrophage activation may be beneficial for CD treatment. In the present study, a series of trifluoroethyl thiazolo[3,2-b] [1,2,4]triazole derivatives were used to investigate their potential anti-inflammatory activities and the underlying mechanism. In a biological activity screen, compound 7# (Thiazolo [3,2-b] [1,2,4]triazole-5-methanamine, 6-phenyl-alpha-(trifluoromethyl)-, (alpha R)-, TT-TFM) suppressed the activation of macrophages. Consistent with the in vitro data, TT-TFM protected against 2,4,6-trinitrobenzene sulfonic acid (TNBS), dextran sulfate sodium (DSS)-induced acute colitis and IL-10 knockout (KO) chronic colitis, as judged by body weight changes and colonic pathological damage. A mechanistic study based on microarray analysis and gene interference experiments indicated that TT-TFM exerted anti-inflammatory effects by enhancing Twist1 expression and subsequently blocking the NF-kappa B/TNF-alpha pathway. In addition, pretreatment with lentiviruses encoding shRNA targeting Twist1 could abolish the therapeutic effect of TT-TFM in TNBS colitis. Ultimately, TT-TFM showed anti-colitis activity by reducing NF-kappa B activation and the TNF-a level by promoting Twist1 expression; thus, TT-TFM may offer a therapeutic strategy for CD patients.

• 出版日期2018-9
• 单位现代配位化学国家重点实验室; 医药生物技术国家重点实验室; 生命分析化学国家重点实验室; 南京大学