Takada Fumito, Kasahara Takahito, Otake Kentaro, Maru Takamitsu, Miwa Masanori, Muto Kei, Sasaki Minoru, Hirozane Yoshihiko, Yoshikawa Masato, Yamaguchi Junichiro
Department of Applied Chemistry, Waseda University, 513 Wasedatsurumakicho, Shinjuku, Tokyo 162-0041, Japan.
Takeda Pharmaceutical Company Limited, 2-26-1 Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan.
ACS Med Chem Lett. 2022 Aug 11;13(9):1421-1426. doi: 10.1021/acsmedchemlett.2c00138. eCollection 2022 Sep 8.
We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time 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 TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, 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 α-synucleinopathy-related diseases.
我们报告了两种化合物TKD150和TKD152的发现，它们通过实时震颤诱导转化（RT-QuIC）测定法促进α-突触核蛋白（aSN）的聚集，以检测异常的aSN。通过利用钯催化的苯并恶唑与碘芳烃的C-H芳基化反应，并在设计中采用平面构象，我们成功鉴定出TKD150和TKD152为aSN的促聚集剂。与先前报道的促聚集剂PA86相比，这两种鉴定出的化合物能够以两倍的速率促进aSN的聚集。将TKD150和TKD152应用于RT-QuIC测定法将缩短固有的延迟时间，并可能使该测定法在临床环境中更广泛地用于诊断α-突触核蛋白病相关疾病。
