Ruthenium(II)-Arene Complexes with a 2,2'-Bipyridine Ligand as Anti-Aβ Agents.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Materials Science

Background:

• Alzheimer's disease is characterized by amyloid-β (Aβ) peptide aggregation.
• Antibody therapeutics targeting Aβ have shown clinical success, renewing interest in Aβ-modulating agents.
• Small molecule metal complexes offer a promising alternative due to their ease of synthesis and modularity.

Purpose of the Study:

• To synthesize and evaluate ruthenium-arene complexes for their ability to modulate Aβ aggregation.
• To investigate the structure-activity relationship of these complexes concerning Aβ aggregation inhibition.
• To assess the biocompatibility and serum albumin affinity of the most promising compounds.

Main Methods:

• Synthesis of ruthenium-arene complexes with varying 2,2-bipyridine ligands.
• Assessment of Aβ aggregation using thioflavin T (ThT) fluorescence assays.
• Analysis of aggregate size using dynamic light scattering (DLS).
• Visualization of aggregate morphology via transmission electron microscopy (TEM).

Main Results:

• Several ruthenium-arene complexes were prepared and tested for their anti-amyloid-β aggregation activity.
• The complex RuBA, featuring a 4,4-diamino-2,2-bipyridine ligand, exhibited the most potent inhibition of Aβ aggregation.
• RuBA demonstrated favorable serum albumin affinity and biocompatibility with neuronal cell lines.
• Structure-activity relationship studies highlighted the crucial role of amino groups on the bipyridine ligand for anti-Aβ activity.

Conclusions:

• Ruthenium-arene complexes, particularly RuBA, are effective modulators of amyloid-β aggregation.
• The presence of amino groups on the bipyridine ligand is critical for the anti-amyloid-β efficacy of these complexes.
• RuBA represents a promising lead compound for further development in Alzheimer's disease therapeutics.