Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 13, Issue 9, Pages 1421-1426Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00138
Keywords
C-H Arylation; alpha-synuclein; proaggregator; RT-QuIC
Categories
Funding
- JSPS KAKENHI [JP JP21H05213, JP20H04829, JP21K05079]
- JST ERATO [JPMJER1901]
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This study reports the discovery of two compounds, TKD 150 and TKD152, that promote the aggregation of aSN. Compared to a previously reported proaggregator, PAS6, these two compounds have a stronger proaggregation effect and can shorten the inherent lag time of the RT-QuIC assay, potentially enabling wider use in the clinical diagnosis of alpha-synucleinopathy-related diseases.
We report the discovery of two compounds, TKD 150 and TKD152, that promote the aggregation of a-synudein (aSN) using a realtime quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TILD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PAS6, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of alpha-synudeinopathy-related diseases.
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