Ruankham Waralee, Songtawee Napat, Prachayasittikul Veda, Worachartcheewan Apilak, Suwanjang Wilasinee, Pingaew Ratchanok, Prachayasittikul Virapong, Prachayasittikul Supaluk, Phopin Kamonrat
Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
ACS Omega. 2023 Nov 30;8(49):46977-46988. doi: 10.1021/acsomega.3c06764. eCollection 2023 Dec 12.
The discovery of novel bioactive molecules as potential multifunctional neuroprotective agents has clinically drawn continual interest due to devastating oxidative damage in the pathogenesis and progression of neurodegenerative diseases. Synthetic 8-aminoquinoline antimalarial drug is an attractive pharmacophore in drug development and chemical modification owing to its wide range of biological activities, yet the underlying molecular mechanisms are not fully elucidated in preclinical models for oxidative damage. Herein, the neuroprotective effects of two 8-aminoquinoline-uracil copper complexes were investigated on the hydrogen peroxide-induced human neuroblastoma SH-SY5Y cells. Both metal complexes markedly restored cell survival, alleviated apoptotic cascades, maintained antioxidant defense, and prevented mitochondrial function by upregulating the sirtuin 1 (SIRT1)/3-FOXO3a signaling pathway. Intriguingly, molecular docking and pharmacokinetic prediction suggested that these synthetic compounds acted as SIRT1 activators with potential drug-like properties, wherein the uracil ligands (5-iodoracil and 5-nitrouracil) were essential for effective binding interactions with the target protein SIRT1. Taken together, the synthetic 8-aminoquinoline-based metal complexes are promising brain-targeting drugs for attenuating neurodegenerative diseases.
由于神经退行性疾病的发病机制和进展过程中存在严重的氧化损伤，发现新型生物活性分子作为潜在的多功能神经保护剂在临床上一直备受关注。合成的8-氨基喹啉抗疟药物因其广泛的生物活性，在药物开发和化学修饰方面是一种有吸引力的药效基团，但其在氧化损伤临床前模型中的潜在分子机制尚未完全阐明。在此，研究了两种8-氨基喹啉-尿嘧啶铜配合物对过氧化氢诱导的人神经母细胞瘤SH-SY5Y细胞的神经保护作用。两种金属配合物均通过上调沉默调节蛋白1（SIRT1）/3-FOXO3a信号通路，显著恢复细胞活力，减轻凋亡级联反应，维持抗氧化防御，并保护线粒体功能。有趣的是，分子对接和药代动力学预测表明，这些合成化合物作为具有潜在类药物性质的SIRT1激活剂，其中尿嘧啶配体（5-碘尿嘧啶和5-硝基尿嘧啶）对于与靶蛋白SIRT1的有效结合相互作用至关重要。综上所述，合成的基于8-氨基喹啉的金属配合物是用于减轻神经退行性疾病的有前景的脑靶向药物。
