Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

Alzheimer’s disease (AD) is
the most common form of dementia,
where one of the pathological hallmarks of AD is extracellular protein
deposits, the primary component of which is the peptide amyloid-β
(Aβ). Recently, the soluble form of Aβ has been recognized
as the primary neurotoxic species, making it an important target for
therapeutic development. Metal-based drugs are promising candidates
to target Aβ, as the interactions with the peptide can be tuned
by ligand design. In the current study, 11 ruthenium complexes containing
pyridine-based ligands were prepared, where the functional groups
at the para position on the coordinated pyridine
ligand were varied to determine structure–activity relationships.
Overall, the complexes with terminal primary amines had the greatest
impact on modulating the aggregation of Aβ and diminishing its
cytotoxicity. These results identify the importance of specific intermolecular
interactions and are critical in the advancement of metal-based drugs
for AD therapy.

阿尔茨海默病（Alzheimer’s disease, AD）是最常见的痴呆类型，其病理特征之一为细胞外蛋白沉积，该沉积的主要成分为β淀粉样蛋白（amyloid-β, Aβ）肽段。近年来，可溶性形式的Aβ被证实为主要的神经毒性物质，因此成为治疗药物研发的重要靶点。金属基药物是靶向Aβ的极具潜力的候选药物，因其与该肽段的相互作用可通过配体设计进行调控。本研究制备了11种含吡啶类配体的钌配合物，通过改变配位吡啶配体对位的官能团以探究构效关系。总体而言，带有末端伯胺基团的配合物在调节Aβ聚集、降低其细胞毒性方面效果最为显著。本研究结果明确了特定分子间相互作用的重要性，对推动用于AD治疗的金属基药物的研发具有关键意义。