Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary.
Center for Pharmacology and Drug Research & Development, Semmelweis University, 26 Üllői út, H-1085 Budapest, Hungary.
Int J Mol Sci. 2024 Oct 20;25(20):11274. doi: 10.3390/ijms252011274.
Numerous beneficial effects of resveratrol were reported; however, its pharmacological profile is contradictious. Previously, we have demonstrated that resveratrol has a dose-dependent cytoprotective effect and the essential role of autophagy induction was demonstrated. Resveratrol suffers from unfavorable pharmacokinetics, hindering its clinical use. Our aim was to study the cytoprotective effect of resveratrol derivatives to better understand structure-activity relationships that may facilitate the development of compounds with better druglike characteristics. Serum-deprivation-induced caspase activation, free radical generation, mitochondrial membrane depolarization and autophagy were detected in the presence of resveratrol analogs with different oxidation states on mouse embryonal fibroblasts. Distinct cytoprotective mechanisms of the examined compounds were revealed. Monomethyl resveratrol had similar potency to resveratrol (EC: 85.3 vs. 84.2 μM); however, autophagy induction was not essential for its cytoprotective effect. Oxyresveratrol was found to be a strong antioxidant that can induce direct cytoprotection rather than autophagy. Trimethyl-resveratrol, lacking free hydroxyl groups, induced damage that was too significant and hardly compensated by the activation of cytoprotective machineries, and caspase activation was reduced by only 24.5%. Based on our results, methylation of resveratrol reduces its antioxidant activity, while autophagy induction can still contribute to its cytoprotective effect. The introduction of an additional hydroxyl group, however, augments the antioxidant properties, inducing cytoprotection without autophagy induction.
已有大量研究报道白藜芦醇具有多种有益作用，但它的药理学特性存在矛盾。此前，我们已经证明白藜芦醇具有剂量依赖性的细胞保护作用，并且诱导自噬的作用至关重要。白藜芦醇的药代动力学性质不佳，阻碍了其临床应用。我们的目的是研究白藜芦醇衍生物的细胞保护作用，以更好地了解结构-活性关系，从而有助于开发具有更好类药性特征的化合物。在存在不同氧化态的白藜芦醇类似物的情况下，检测血清剥夺诱导的 caspase 激活、自由基生成、线粒体膜去极化和自噬在小鼠胚胎成纤维细胞中。研究表明，所研究的化合物具有不同的细胞保护机制。单甲基白藜芦醇与白藜芦醇具有相似的效力（EC：85.3 对 84.2 μM）；然而，自噬诱导不是其细胞保护作用所必需的。发现氧白藜芦醇是一种强大的抗氧化剂，可诱导直接的细胞保护作用而不是自噬。三甲基白藜芦醇缺乏游离羟基基团，引起的损伤太大，难以通过激活细胞保护机制来补偿，并且 caspase 激活仅减少 24.5%。基于我们的结果，白藜芦醇的甲基化降低了其抗氧化活性，而自噬诱导仍然可以为其细胞保护作用做出贡献。然而，引入额外的羟基基团会增强抗氧化性能，在不诱导自噬的情况下诱导细胞保护。
