Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain.
Faculty of Health, Camilo José Cela University, Castillo de Alarcón 49, Villanueva de la Cañada, 28692 Madrid, Spain.
Int J Mol Sci. 2022 Mar 21;23(6):3411. doi: 10.3390/ijms23063411.
Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named -. The neuroprotective properties of nitrones, -, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, -, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone () and are similar to N-acetyl-L-cysteine (), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones , , B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones , ). All of these possess EC values in the range of 1-6 μM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone , B = thymine) or hard halogen substituents such as Br and Cl (nitrones , , B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (ECs ≈ 2-4 μM) and antioxidant (ECs ≈ 0.4-3.5 μM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, , , , presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at and (bis-nitronas , ) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (, ) and pyrimidine (, ) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.
本文报道了一些命名为 - 的基于核苷的硝酮的合成、抗氧化和神经保护特性。使用人神经母细胞瘤 SH-SY5Y 细胞，通过体外氧葡萄糖剥夺缺血模型测量硝酮 - 的神经保护特性。我们的结果表明，硝酮 - 具有比 α-苯-N-叔丁基硝酮（）更好的神经保护和抗氧化特性，并且与 N-乙酰-L-半胱氨酸（）相似，后者是一种众所周知的抗氧化和神经保护剂。具有最高神经保护能力的硝酮是那些含有嘌呤核苷碱基的硝酮（硝酮 - ，B = 腺嘌呤，茶碱），其次是嘧啶核苷碱基带有 H 或 F 取代基的 C5 位的硝酮（硝酮 - ）。所有这些都具有 1-6 μM 的 EC 值和高于 100%的最大活性。然而，引入甲基取代基（硝酮 - ，B = 胸腺嘧啶）或硬卤素取代基（如 Br 和 Cl）（硝酮 - ，B = 5-Br 和 5-Cl 尿嘧啶，分别）会降低具有尿嘧啶作为碱基的硝酮的神经保护活性（）。通过对这些化合物在超氧自由基产生方面的高抗坏死（ECs ≈ 2-4 μM）和抗氧化（ECs ≈ 0.4-3.5 μM）活性的研究结果，证实了对整体代谢细胞能力的影响。一般来说，所有测试的硝酮都是培养的神经母细胞瘤细胞中超氧自由基产生的优秀抑制剂，也是有效的羟基自由基清除剂，可抑制体外脂质过氧化，特别是，，，，在测试的硝酮中表现出最高的脂氧合酶抑制活性。最后，在 （双硝酮 - ）的和位引入两个硝酮基团并没有比它们的前体单硝酮表现出更好的神经保护作用。这些结果使我们提出含有嘌呤（，）和嘧啶（，）核苷碱基的硝酮作为治疗脑缺血和/或神经退行性疾病的潜在治疗剂，我们进一步使用这些疾病的体内模型研究了它们的作用。
