There is a growing interest in the search for metal-based therapeutics for protein misfolding disorders such as Alzheimer’s disease (AD). A novel and largely unexplored class of metallodrugs is constituted by paddlewheel diruthenium complexes, which exhibit unusual water solubility and stability and unique coordination modes to proteins. Here, we investigate the ability of the complexes [Ru₂Cl(DPhF)(O₂CCH₃)₃]·H₂O (1), [Ru₂Cl(DPhF)₂(O₂CCH₃)₂]·H₂O (2), and K₂[Ru₂(DPhF)(CO₃)₃]·3H₂O (3) (DPhF^– = N,N′-diphenylformamidinate) to interfere with the amyloid aggregation of the Aβ_1–42 peptide. These compounds differ in charge and steric hindrance due to the coordination of a different number of bulky ligands. The mechanisms of action of the three complexes were studied by employing a plethora of physicochemical and biophysical techniques as well as cellular assays. All these studies converge on different mechanisms of inhibition of amyloid fibrillation: complexes 1 and 2 show a clear inhibitory effect due to an exchange ligand process in the Ru₂ unit aided by aromatic interactions. Complex 3 shows no inhibition of aggregation, probably due to its negative charge in solution. This study demonstrates that slight variations in the ligands surrounding the bimetallic core can modulate the amyloid aggregation inhibition and supports the use of paddlewheel diruthenium complexes as promising therapeutics for Alzheimer’s disease.

中文翻译：

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二钌配合物抑制 Aβ1-42 聚集机制的比较分析


人们对寻找基于金属的治疗阿尔茨海默氏病 (AD) 等蛋白质错误折叠疾病的疗法越来越感兴趣。一类新型且很大程度上未经探索的金属药物由叶轮二钌络合物构成，其表现出不寻常的水溶性和稳定性以及与蛋白质的独特配位模式。在这里，我们研究了配合物 [Ru ₂ Cl(DPhF)(O ₂ CCH ₃ ) ₃ ]·H 的能力 ₂ O (1)，[Ru ₂ Cl(DPhF) ₂ (O ₂ CCH ₃ ) ₂ ]·H ₂ O (2)，和 K ₂ [Ru ₂ (DPhF)(CO ₃ ]·3H ₂ O (3) (DPhF ^– = N,N'-二苯基甲脒)干扰 Aβ 的淀粉样蛋白聚集 _1–42 肽。由于不同数量的大配体的配位，这些化合物的电荷和空间位阻不同。通过采用大量的物理化学和生物物理技术以及细胞测定来研究这三种复合物的作用机制。所有这些研究都集中在抑制淀粉样纤维颤动的不同机制上：由于 Ru ₂ 单元中芳香族相互作用辅助的交换配体过程，复合物 1 和 2 显示出明显的抑制作用。复合物 3 没有显示出对聚集的抑制作用，这可能是由于其在溶液中带有负电荷。这项研究表明，双金属核心周围配体的轻微变化可以调节淀粉样蛋白聚集抑制，并支持使用桨轮二钌配合物作为阿尔茨海默病的有希望的治疗方法。