Ohlow Maike J, Sohre Selina, Granold Matthias, Schreckenberger Mathias, Moosmann Bernd
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55099, Mainz, Germany.
Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, 55131, Mainz, Germany.
Pharm Res. 2017 Feb;34(2):378-393. doi: 10.1007/s11095-016-2068-0. Epub 2016 Nov 28.
Only a fraction of the currently established low-molecular weight antioxidants exhibit cytoprotective activity in living cells, which is considered a prerequisite for their potential clinical usefulness in Parkinson's disease or stroke. Post hoc structure-activity relationship analyses have predicted that increased lipophilicity and enhanced radical stabilization could contribute to such cytoprotective activity.
We have synthesized a series of novel phenothiazine-type antioxidants exhibiting systematic variation in their lipophilicity and radical stabilization. Phenothiazine was chosen as lead structure for its superior activity at baseline. The novel compounds were evaluated for their neuroprotective potency in cell culture, and for their primary molecular targets.
Lipophilicity was associated with enhanced cytoprotective activity, but only to a certain threshold (logP ≈ 7). Benzannulation likewise produced improved cytoprotectants that exhibited very low EC values of ~8 nM in cultivated neuronal cells. Inhibition of global protein oxidation was the best molecular predictor of cytoprotective activity, followed by the inhibition of membrane protein autolysis. In contrast, the inhibition of lipid peroxidation in isolated brain lipids and the suppression of intracellular oxidant accumulation were poor predictors of cytoprotective activity, primarily as they misjudged the cellular advantage of high lipophilicity.
Lipophilicity, radical stabilization and molecular weight appear to form an uneasy triangle, in which a slightly faulty selection may readily abolish neuroprotective activity.
目前已确定的低分子量抗氧化剂中，只有一小部分在活细胞中表现出细胞保护活性，这被认为是它们在帕金森病或中风中具有潜在临床应用价值的前提条件。事后的构效关系分析预测，亲脂性增加和自由基稳定性增强可能有助于这种细胞保护活性。
我们合成了一系列新型吩噻嗪类抗氧化剂，它们在亲脂性和自由基稳定性方面呈现出系统变化。选择吩噻嗪作为先导结构是因为其在基线时具有优异的活性。对这些新型化合物进行了细胞培养中的神经保护效力及其主要分子靶点的评估。
亲脂性与增强的细胞保护活性相关，但仅到一定阈值（logP≈7）。苯并环化同样产生了改进的细胞保护剂，其在培养的神经元细胞中表现出极低的EC值，约为8 nM。抑制整体蛋白质氧化是细胞保护活性的最佳分子预测指标，其次是抑制膜蛋白自溶。相比之下，抑制离体脑脂质中的脂质过氧化和抑制细胞内氧化剂积累是细胞保护活性的较差预测指标，主要是因为它们错误地判断了高亲脂性的细胞优势。
亲脂性、自由基稳定性和分子量似乎形成了一个不稳定的三角关系，其中稍有错误的选择可能很容易消除神经保护活性。
