Department of Biochemistry and Molecular Pharmacology, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016 Armilla, Granada, Spain.
Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, 18016 Armilla, Granada, Spain.
Eur J Med Chem. 2018 Feb 25;146:123-138. doi: 10.1016/j.ejmech.2018.01.037. Epub 2018 Jan 17.
Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6'-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug.
白藜芦醇是一种天然存在的芪类化合物，已显示出作为几种神经退行性疾病治疗方法的有希望的结果。然而，由于其低功效和生物利用度，其应用受到限制。在这里，我们设计并合成了烷基化白藜芦醇前药，将结构修饰结合起来以改善抗氧化和抗炎特性，并制备前药以延长药物的生物利用度。为了比较，我们还研究了白藜芦醇前药和烷基化白藜芦醇衍生物。甲基化和丁基化白藜芦醇衍生物表现出最佳的体外神经保护和抗炎活性。这些衍生物的葡萄糖基和葡萄糖基酰基前药在斑马鱼胚胎上表现出较低的毒性。当在戊四唑挑战的斑马鱼上检查神经保护作用时，它们能够逆转神经元损伤，但程度低于白藜芦醇。尽管如此，3-O-(6'-O-辛酰基)-β-d-吡喃葡萄糖苷白藜芦醇（化合物 8）使 AChE 活性恢复超过 100％，而白藜芦醇仅恢复至 92％。在亨廷顿病的 3-硝基丙酸小鼠模型中，白藜芦醇衍生物 8 通过改善运动活性和防止体重减轻，延迟了 HD 样症状的发作并减轻了其严重程度。其作用涉及抗氧化作用相当，但优于白藜芦醇，如脑组织中 SOD2 表达和循环中 IL-6 水平（分别为 11 与 18 pg/mL）所示。最后，化合物 8 中的辛酰链可能在炎症和神经元发育中起作用，表明它可能作为双重药物而不是前药起作用。
