Misiu Naitė Indrė, Mikalauskaitė Kamilė, Paulauskaitė Martyna, Sniečkutė Ru Ta, Smirnovas Vytautas, Brukštus Algirdas, Žiaunys Mantas, Žutautė Ieva
Institute of Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko st. 24, Vilnius LT-03225, Lithuania.
Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania.
ACS Chem Neurosci. 2024 Dec 18;15(24):4418-4430. doi: 10.1021/acschemneuro.4c00451. Epub 2024 Nov 27.
Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders in the human body. Specifically, Parkinson's disease is associated with the aggregation of alpha-synuclein. However, current treatments for Parkinson's primarily focus on managing motor symptoms and slowing disease progression. Efforts to prevent and halt the progression of these diseases involve the search for small molecular compounds. In this work, we synthesized imidazo[2,1-][1,3]thiazines in an atom-economic way by cyclization of 2-alkynylthioimidazoles using 10% AuCl as the catalyst. We identified several compounds with specific functional groups capable of both inhibiting the aggregation of alpha-synuclein and redirecting the fibril formation pathway. The investigation into how these substances function revealed that imidazo[2,1-][1,3]thiazine derivatives can influence alpha-synuclein aggregation in several ways. They not only inhibit the primary nucleation process and maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species of alpha-synuclein and cause the formation of fibrils with unique structures and forms. These imidazo[2,1-][1,3]thiazines could potentially be used in developing highly efficient, small molecular weight protein aggregation inhibitors.
不溶性淀粉样原纤维在器官和组织的细胞间隙中积累，导致人体出现各种与淀粉样变性相关的疾病。具体而言，帕金森病与α-突触核蛋白的聚集有关。然而，目前帕金森病的治疗主要集中在控制运动症状和减缓疾病进展。预防和阻止这些疾病进展的努力包括寻找小分子化合物。在这项工作中，我们以原子经济的方式，使用10%的AuCl作为催化剂，通过2-炔硫基咪唑的环化反应合成了咪唑并[2,1-][1,3]噻嗪。我们鉴定出了几种具有特定官能团的化合物，它们既能抑制α-突触核蛋白的聚集，又能改变纤维形成途径。对这些物质作用方式的研究表明，咪唑并[2,1-][1,3]噻嗪衍生物可以通过多种方式影响α-突触核蛋白的聚集。它们不仅抑制初级成核过程，维持向非聚集蛋白状态的平衡，还能稳定α-突触核蛋白的较小寡聚体，并导致形成具有独特结构和形态的纤维。这些咪唑并[2,1-][1,3]噻嗪有可能用于开发高效、小分子量的蛋白质聚集抑制剂。
