作为Aβ42聚集的强效调节剂的新型吩噻嗪衍生物的设计、合成和评价
Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation.
摘要(中文译文)
设计、合成并评价了一类新型稠合三环吩硒嗪衍生物，该类衍生物具有氧化还原活性的硒原子，可作为具有抗氧化活性的Aβ42聚集抑制剂。荧光聚集动力学研究、电子显微镜检查以及小鼠海马HT22神经元细胞和BV2小胶质细胞的细胞学研究证实，这些化合物对Aβ42聚集具有显著抑制作用。化合物5i和9g对Aβ42聚集表现出强效抑制作用，IC50值分别为350 nM和317 nM，其中化合物9g对预先形成的Aβ42纤维具有异常强的解聚能力（IC50 = 210 nM），优于对照化合物白藜芦醇和亚甲蓝。5i和9g均显示出高效的血脑屏障通透性，对Aβ42诱导的细胞毒性提供显著神经保护作用，并通过保护小鼠海马HT22细胞免受过氧化氢诱导的细胞毒性而表现出强抗氧化特性。总之，我们的结果表明，这些新型吩硒嗪类化合物代表了一类有前景的阿尔茨海默病治疗药物。
Abstract
A novel class of fused tricyclic phenoselenazine derivatives possessing a redox-active selenium atom were designed, synthesized, and evaluated as Aβ42 aggregation inhibitors with antioxidant activity. They exhibit remarkable inhibition of Aβ42 aggregation as confirmed by fluorescence aggregation kinetics study, electron microscopy, and cell-based studies in mouse hippocampal HT22 neuronal and BV2 microglial cells. Compounds 5i and 9g exhibited potent inhibition of Aβ42 aggregation with IC50 values of 350 and 317 nM, respectively, with compound 9g exhibiting exceptional ability to destabilize preformed Aβ42 fibrils (IC50 = 210 nM), surpassing those of the reference compounds resveratrol and methylene blue. Both 5i and 9g showed efficient blood-brain barrier permeability and provided significant neuroprotection toward Aβ42-induced cytotoxicity and demonstrated strong antioxidant properties by conferring protection toward hydrogen peroxide-induced cytotoxicity in mouse hippocampal HT22 cells. Collectively, our results demonstrate that these novel phenoselenazines represent a promising class of therapeutics to treat Alzheimer's disease.
如何引用
AMA
Ahmed A Hefny, Rahul C Karuturi, Chandra Mouli R Madhuranthakam, Praveen P N Rao. Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c01959.
APA
Ahmed A Hefny, Rahul C Karuturi, Chandra Mouli R Madhuranthakam, Praveen P N Rao (2026). Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c01959
GB/T 7714
Ahmed A Hefny, Rahul C Karuturi, Chandra Mouli R Madhuranthakam, Praveen P N Rao. Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c01959.
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