合成和细胞毒性评价的Denitroaristolochic酸:结构洞察力和机制的影响在毒性
Jianfei Gao1, Mengtong Zhao1, Jianhua Su1
1Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, China.
Biomolecules
|July 29, 2025
概括
已经建立了为denitroaristolochic酸 (DAA-II-V) 的合成途径. 虽然与阿里斯托洛希克酸I相比,毒性降低了,但化衍生物仍然显示出细胞毒性潜力,这表明除了DNA添加物之外还有其他毒性机制.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 毒理学 毒理学 毒理学
背景情况:
- 阿里斯托洛希克酸 (AA) 具有毒性和致癌性,主要与DNA adduct形成有关.
- 基组和其他结构特征在AA毒性中的作用仍然不完全理解.
- 酸酸 (DAA) 为研究结构毒性关系提供了一个有价值的模型.
研究的目的:
- 为了开发有效的合成路径为denitroaristolochic酸II-V (DAA-II-V).
- 评估DAA-II-V在人类脏靠近管状上皮细胞中的细胞毒性概况.
- 阐明DAA类型的结构-活性关系和潜在的毒性机制.
主要方法:
- 模块化合成利用苏苏基-米亚乌拉合,维蒂格反应和弗里德尔-克拉夫特循环.
- 过程优化以提高关键中间体和最终循环化步骤的产量.
- CCK-8细胞毒性测定用于确定IC50值和评估细胞毒性.
- 使用NMR和质谱学进行结构确认.
主要成果:
- 实现了DAA-II-V的高效合成,对关键循环化实现了高达88.4%的优化产量.
- DAA-III 和 DAA-IV 呈现中度细胞毒性 (IC50 371 μM 和 515 μM),明显低于AA-I (270 μM).
- DAA-II和DAA-V没有显示可检测的细胞毒性,并且发现基组对毒性无关紧要.
结论:
- 缺少基组可以减弱但不能消除阿里斯托洛基酸类型的毒性.
- 酸衍生物中的细胞毒性可能涉及除了DNA附加物形成之外的其他机制,例如氧化应激.
- 这些发现挑战了传统的毒性范式,并为AA模拟研究和阿里斯托罗基亚系植物的安全评估提供了见解.
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