Jung Yuna, Kwon Chaesun, Kim Taeyeon, Lee Jin Woo, Shin Min-Kyoo, Shim Sang Hee
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826 Republic of Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826 Republic of Korea.
Mar Life Sci Technol. 2023 Nov 20;6(1):84-92. doi: 10.1007/s42995-023-00198-7. eCollection 2024 Feb.
Tetramic acid-containing natural products are attracting significantly increasing attention from biologists and chemists due to their intriguing structures and biological activities. In the present study, two new tetramic acid alkaloids tolypyridone I () and tolypyridone J (), together with five known ones (-), were isolated from cultures of a marine fungus FB06 isolate obtained from a marine sediment in Beaufort sea of North Alaska. Their structures were elucidated using 1D, 2D NMR, and HRESIMS. Their configurations were established on the basis of H coupling constants, ROESY correlations and DP4 calculations. Compound was isolated as mixtures of rotational isomers with C-3 to C-7 axis between 4-hydroxy-2-pyridone and 1-ethyl-3,5-dimethylcyclohexane, hindering rotation. In our unbiased screening to discover neuroprotective compounds in an in vitro Parkinson's disease (PD) model, SH-SY5Y dopaminergic cells were treated with isolated compounds followed by treatment with 1-methyl-4-phenylpyridinium (MPP), a parkinsonian neurotoxin. Among tested compounds, F-14329 () significantly protected cells from MPP-induced cytotoxicity. MPP-mediated cell death is known to be related to the regulation of Bcl-2 family proteins, specifically the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax levels. Treatment with 2 mmol/L of MPP for 24 h significantly reduced Bcl-2 levels compared to control treated with vehicle. However, treatment with F-14329 () attenuated such reduction. This study demonstrates that tetramic acid-motif compounds could be potential lead compounds for treating PD.
The online version contains supplementary material available at 10.1007/s42995-023-00198-7.
含四嗪酸的天然产物因其引人入胜的结构和生物活性而受到生物学家和化学家越来越多的关注。在本研究中，从阿拉斯加北部波弗特海海洋沉积物中获得的海洋真菌FB06菌株的培养物中分离出两种新的四嗪酸生物碱甲苯吡啶酮I（）和甲苯吡啶酮J（），以及五种已知的生物碱（-）。使用一维、二维核磁共振和高分辨电喷雾电离质谱对它们的结构进行了阐明。根据氢耦合常数、旋转 Overhauser 效应光谱相关和 DP4 计算确定了它们的构型。化合物以4-羟基-2-吡啶酮和1-乙基-3,5-二甲基环己烷之间具有C-3至C-7轴的旋转异构体混合物形式分离出来，阻碍了旋转。在我们在体外帕金森病（PD）模型中发现神经保护化合物的无偏筛选中，用分离出的化合物处理SH-SY5Y多巴胺能细胞后，再用帕金森神经毒素1-甲基-4-苯基吡啶鎓（MPP）处理。在测试的化合物中，F-14329（）显著保护细胞免受MPP诱导的细胞毒性。已知MPP介导的细胞死亡与Bcl-2家族蛋白的调节有关，特别是抗凋亡Bcl-2的下调和促凋亡Bax水平的上调。与用赋形剂处理的对照相比，用2 mmol/L的MPP处理24小时显著降低了Bcl-2水平。然而，用F-14329（）处理减弱了这种降低。这项研究表明，四嗪酸基序化合物可能是治疗PD的潜在先导化合物。
在线版本包含可在10.1007/s42995-023-00198-7获取的补充材料。
