Synthesis and evaluation of (+)-decursin derivatives as inhibitors of the Wnt/β-catenin pathway

• Published in: Bioorganic & medicinal chemistry letters 2016-08, Vol.26 (15), p.3529-3532
• Main Authors: Lee, Jee-Hyun, Kim, Min-Ah, Park, Seoyoung, Cho, Soo-Hyun, Yun, Eunju, O, Yu-Seok, Kim, Jiseon, Goo, Ja-Il, Yun, Mi-Young, Choi, Yongseok, Oh, Sangtaek, Song, Gyu-Yong
• Format: Article
• Language: English
• Subjects: Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Butyrates - chemical synthesis; Butyrates - chemistry; Butyrates - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cinnamoyl decursin; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Phenylpropionyl decursin; Prostate cancer; Protein degradation; Stereoisomerism; Structure-Activity Relationship; Wnt Proteins - antagonists & inhibitors; Wnt Proteins - metabolism; Wnt/β-catenin pathway
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.06.029

[Display omitted] We synthesized (+)-decursin derivatives substituted with cinnamoyl- and phenyl propionyl groups originating from (+)-CGK062 and screened them using a cell-based assay to detect relative luciferase reporter activity. Of this series, compound 8b, in which a 3-acetoxy cinnamoyl group was introduced, most potently inhibited (97.0%) the Wnt/β-catenin pathway. Specifically, compound 8b dose-dependently inhibited Wnt3a-induced expression of the β-catenin response transcription (CRT) and increased β-catenin degradation in HEK293 reporter cells. Furthermore, compound 8b suppressed expression of the downstream β-catenin target genes cyclin D1 and c-myc and suppressed PC3 cell growth in a concentration-dependent manner.