Alzheimer’s disease (AD) is the most common form of dementia, and up to now, there are no disease-modifying drugs available. Natural product hybrids based on the flavonoid taxifolin and phenolic acids have shown a promising pleiotropic neuroprotective profile in cell culture assays and even disease-modifying effects in vivo. However, the detailed mechanisms of action remain unclear. To elucidate the distinct intracellular targets of 7-O-esters of taxifolin, we present in this work the development and application of a chemical probe, 7-O-cinnamoyltaxifolin-alkyne, for target identification using activity-based protein profiling. 7-O-Cinnamoyltaxifolin-alkyne remained neuroprotective in all cell culture assays. Western blot analysis showed a comparable influence on the same intracellular pathways as that of the lead compound 7-O-cinnamoyltaxifolin, thereby confirming its suitability as a probe for target identification experiments. Affinity pulldown and MS analysis revealed adenine nucleotide translocase 1 (ANT-1) and sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) as intracellular interaction partners of 7-O-cinnamoyltaxifolin-alkyne and thus of 7-O-esters of taxifolin.

中文翻译：

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基于神经保护性类黄酮杂化物的化学探针的开发与应用

阿尔茨海默氏病（AD）是痴呆症最常见的形式，到目前为止，尚无可改善疾病的药物。基于黄酮类生物碱和酚酸的天然产物杂合体在细胞培养测定中显示出有希望的多效性神经保护作用，甚至在体内具有改善疾病的作用。但是，具体的作用机制仍不清楚。为了阐明滑石粉7- O-酯的不同细胞内靶标，我们在这项工作中介绍了化学探针7 - O-肉桂酰基紫杉醇-炔烃的开发和应用，用于使用基于活性的蛋白质谱进行靶标鉴定。7 Ø-肉桂酰基紫杉醇-炔在所有细胞培养测定中均保持神经保护作用。蛋白质印迹分析显示与前导化合物7- O-肉桂酰基紫杉酚对相同的细胞内途径具有可比的影响，从而证实了其适合作为靶标鉴定实验的探针。亲和力下拉和MS分析显示，腺嘌呤核苷酸转位酶1（ANT-1）和肌浆网/内质网Ca ²⁺ ATPase（SERCA）是7 - O-肉桂酰基紫杉醇-炔烃的胞内相互作用伴侣，因此是士福林的7- O-酯。