School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
School of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
Eur J Med Chem. 2021 Oct 15;222:113554. doi: 10.1016/j.ejmech.2021.113554. Epub 2021 May 29.
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3β (GSK-3β) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3β/DYRK1A inhibitors, we focused on harmine, a natural β-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3β/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3β and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3β and DYRK1A with IC values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3β and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.
阿尔茨海默病（AD）是一种慢性进行性神经退行性疾病，其特征为认知功能不可逆转损害、记忆丧失和行为障碍，最终导致死亡。糖原合酶激酶 3β（GSK-3β）和双特异性酪氨酸磷酸化调节激酶 1A（DYRK1A）因其在tau 病理学中的作用而受到广泛关注。为了寻找潜在的双 GSK-3β/DYRK1A 抑制剂，我们专注于天然β-咔啉生物碱 harmine，它在预防 AD 方面具有多种生物学作用，已被广泛研究。在这项研究中，设计、合成了一系列新的 harmine 衍生物，并将其作为双 GSK-3β/DYRK1A 抑制剂进行评估，以评估其多种生物学活性。体外结果表明，它们中的大多数对 GSK-3β 和 DYRK1A 表现出有希望的活性。其中，化合物 ZDWX-25 对 GSK-3β 和 DYRK1A 的抑制作用较强，IC 值分别为 71 和 103 nM。分子模拟和动力学研究证实，ZDWX-25 可以与 GSK-3β 和 DYRK1A 的 ATP 结合口袋相互作用。Western blot 分析表明，ZDWX-25 可抑制 OKA 诱导的 SH-SY5Y 细胞中 tau 蛋白的过度磷酸化。此外，ZDWX-25 在体外具有良好的血脑屏障通透性。更重要的是，ZDWX-25 可以改善 APP/PS1/Tau 转基因小鼠的学习和记忆障碍。这些结果表明，基于 harmine 的化合物可能成为治疗 AD 的有前途的双重靶向候选药物。
