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发现和优化1,2,4-triazole衍生物作为新的铁灭抑制剂

Jiawei Zhang¹, Fang Lin¹, Yijie Xiao¹

¹Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology and Department of Cancer Center of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.

European journal of medicinal chemistry

|December 25, 2024

概括

研究人员发现了新型的1,2,4-triazole衍生物,可以抑制铁亡,这是一种涉及癌症和器官损伤等疾病的细胞死亡途径. 化合物NY-26显示出作为治疗剂的巨大潜力.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
药理学药理学是指药理学的学科.

背景情况:

铁亡是一种受调节的细胞死亡机制,由依赖铁的脂质活性氧物种 (ROS) 积累驱动.
这种细胞死亡途径与各种疾病有关,包括急性器官损伤,神经退行性疾病和癌症.
目前的铁灭抑制剂在临床转化中面临挑战,原因是疗效不足或药物动力学性能差.

研究的目的:

从化合物库中识别新的铁灭抑制剂.
评估新发现的1,2,4-triazole衍生物的治疗潜力.
在疾病模型中研究化合物的作用机制和疗效.

主要方法:

内部化合物库的表型选,以确定铁灭抑制剂.
在体外评估使用RSL3诱导的ferroptosis在786-O细胞中的化合物活性.
在多个细胞系中验证抗费洛普托特活性.
机理学研究以阐明作用模式.
在ConA诱导的急性肝损伤小鼠模型中的体内评估.

主要成果:

几种1,2,4-triazole衍生物被确定为强大的铁灭抑制剂.
化合物NY-26以纳米分子强度 (EC50 = 62 nM) 显著抑制了铁化.
NY-26通过捕捉自由基来起作用,作为一种内在的抗氧化剂.
鉴定的三醇衍生物改善了急性肝损伤的小鼠模型中的病理状况.

结论:

基于一种新的1,2,4-triazole支架的NY-26是一种有前途的铁灭抑制剂.
该化合物表现出强烈的抗铁菌活性和有利的作用机制.
NY-26 具有重要的治疗潜力,用于治疗与铁死相关的疾病,需要进一步研究.

关键词:

1,2,4-三醇衍生物 1,2,4-三醇衍生物铁化抑制剂铁化抑制剂抗氧化剂捕捉激进分子的抗氧化剂结构与活动的关系.

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