CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal.
CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal; Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, 4200-072, Porto, Portugal.
Eur J Med Chem. 2022 Dec 5;243:114740. doi: 10.1016/j.ejmech.2022.114740. Epub 2022 Sep 8.
Increased oxidative stress (OS) and depletion of nigrostriatal dopamine (DA) are closely linked to the neurodegeneration observed in Parkinson's Disease (PD). Caffeic acid (CA)-based antioxidants were developed, and their inhibitory activities towards monoamine oxidases (MAOs) and catechol O-methyltransferases (COMT) were screened. The results showed that the incorporation of an extra double bond maintained or even boosted the antioxidant properties of CA. α-CN derivatives displayed redox potentials (E) similar to CA (1) and inhibited hMAO-B with low μM IC values. Moreover, catechol amides acted as MB-COMT inhibitors, showing IC values within the low μM range. In general, CA derivatives presented safe cytotoxicity profiles at concentrations up to 10 μM. The formation of reactive oxygen species (ROS) induced by CA derivatives may be underlying the cytotoxic effects observed at higher concentrations. Catechol amides 3-6, 8-11 at 10 μM protected cells against oxidative damage. Compounds 3 and 8 were predicted to cross the blood-brain barrier (BBB) by passive diffusion. In summary, we report for the first time BBB-permeant CA-based multitarget lead compounds that may restore DAergic neurotransmission (dual hMAO-B/MB-COMT inhibition) and prevent oxidative damage. The data represents a groundbreaking advancement towards the discovery of the next generation of new drugs for PD.
氧化应激（OS）增加和黑质纹状体多巴胺（DA）耗竭与帕金森病（PD）中观察到的神经退行性变密切相关。开发了基于咖啡酸（CA）的抗氧化剂，并筛选了它们对单胺氧化酶（MAO）和儿茶酚-O-甲基转移酶（COMT）的抑制活性。结果表明，额外双键的结合保持甚至增强了 CA 的抗氧化性能。α-CN 衍生物显示出与 CA（1）相似的氧化还原电位（E），并以低 μM IC 值抑制 hMAO-B。此外，儿茶酚酰胺作为 MB-COMT 抑制剂，IC 值在低 μM 范围内。一般来说，CA 衍生物在高达 10 μM 的浓度下呈现出安全的细胞毒性谱。在较高浓度下观察到的细胞毒性可能是 CA 衍生物诱导活性氧（ROS）形成的结果。儿茶酚酰胺 3-6、8-11 在 10 μM 时可保护细胞免受氧化损伤。预测化合物 3 和 8 可通过被动扩散穿过血脑屏障（BBB）。总之，我们首次报道了可透过血脑屏障的基于 CA 的多靶标先导化合物，它们可能恢复 DA 能神经传递（双重 hMAO-B/MB-COMT 抑制）并预防氧化损伤。该数据代表了朝着发现新一代 PD 新药迈出的开创性一步。
