Coordination of Anle138b to Silver Results in Selective Reduction of a C‐Terminal Truncated α‐Synuclein Protein and Increased Aggregate Size

Parkinson's disease (PD) is a prevalent age‐related neurodegenerative syndrome, partially thought to be caused by a decrease in α‐synuclein proteostasis. Anle138b = 5‐(1,3‐benzodioxol‐5‐yl)‐3‐(3‐bromophenyl)‐1 H ‐pyrazole ( HL ) is undergoing clinical trials as a promising mitigator of α‐synuclein aggregation. Because complexation to metals is known to modulate the activity of several drugs, we have prepared and characterized: H 2 L(ClO 4 ) , [Cu I ( µ ‐L)] 3 , and [Ag I ( µ ‐L)] 3 . To better understand the bioviability of these compounds, we monitored their effects in a cell culture model of α‐synuclein protein aggregation using human α‐synuclein preformed fibrils (PFFs). Using two different anti‐α‐synuclein antibodies, our data suggest that [Ag I ( µ ‐L)] 3 decreases a C‐terminal truncated protein that is approximately 12.4 kDa, as well as increases the size and alters the shape of PFF‐induced aggregates. This indicates that [Ag I ( µ ‐L)] 3 impacts aggregation in a manner different from HL and may serve as a novel tool for studying C‐terminal truncation‐related aggregation chemistry.