Laboratory of Growth Regulators, Faculty of Science, Palacký University and the Institute of Experimental Botany of the Czech Academy of Sciences, Šlechtitelů 27, CZ-78371, Olomouc, Czech Republic; Department of Neurology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacký University Olomouc, CZ-775 20, Olomouc, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Palacky University, 17. Listopadu 1192/12, 771 46, Olomouc, Czech Republic.
Eur J Med Chem. 2021 Mar 5;213:113168. doi: 10.1016/j.ejmech.2021.113168. Epub 2021 Jan 16.
Novel triterpene derivatives were prepared and evaluated in salsolinol (SAL)- and glutamate (Glu)-induced models of neurodegeneration in neuron-like SH-SY5Y cells. Among the tested compounds, betulin triazole 4 bearing a tetraacetyl-β-d-glucose substituent showed a highly potent neuroprotective effect. Further studies revealed that removal of tetraacetyl-β-d-glucose part (free triazole derivative 10) resulted in strong neuroprotection in the SAL model at 1 μM, but this derivative suffered from cytotoxicity at higher concentrations. Both compounds modulated oxidative stress and caspase-3,7 activity, but 10 showed a superior effect comparable to the Ac-DEVD-CHO inhibitor. Interestingly, while both 4 and 10 outperformed the positive controls in blocking mitochondrial permeability transition pore opening, only 4 demonstrated potent restoration of the mitochondrial membrane potential (MMP) in the model. Derivatives 4 and 10 also showed neuroprotection in the Glu model, with 10 exhibiting the strongest oxidative stress reducing effect among the tested compounds, while the neuroprotective activity of 4 was probably due recovery of the MMP.
新型三萜衍生物在神经元样 SH-SY5Y 细胞中进行的嗜银蛋白（SAL）和谷氨酸（Glu）诱导的神经退行性变模型中进行了制备和评估。在所测试的化合物中，具有四乙酰基-β-d-葡萄糖取代基的白桦脂三唑 4 表现出高度有效的神经保护作用。进一步的研究表明，去除四乙酰基-β-d-葡萄糖部分（游离三唑衍生物 10）在 1μM 时可在 SAL 模型中产生强烈的神经保护作用，但该衍生物在较高浓度下会产生细胞毒性。这两种化合物均调节氧化应激和 caspase-3、7 活性，但 10 的作用优于与 Ac-DEVD-CHO 抑制剂相当。有趣的是，虽然 4 和 10 都优于阳性对照物，可阻止线粒体通透性转换孔的打开，但只有 4 表现出在该模型中有效恢复线粒体膜电位（MMP）的作用。衍生物 4 和 10 也在 Glu 模型中表现出神经保护作用，其中 10 在测试的化合物中表现出最强的降低氧化应激作用，而 4 的神经保护活性可能归因于 MMP 的恢复。
