Efficient synthesis of heterocyclic flavonoids with hedgehog signal inhibitory activity

Midori A. Arai, Takao Utsumi, Natsuki Yanase, Teruhisa Fujimatsu, Masami Ishibashi

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


The hedgehog (Hh) signaling pathway performs important roles in embryonic development and cellular proliferation and differentiation. However, in many cancer cells Hh signaling is aberrantly activated, which has provided a strong impetus for the development of Hh pathway inhibitors. To address this, we synthesized a series of heterocyclic flavonoids and evaluated their Hh signaling inhibitory activity on cancer cell lines using our cell-based assay system. Of the synthetic flavonoids, compounds 4a and g showed good inhibitory activity (IC50 was 16.8 and 21.8µM, respectively), and were cytotoxic toward human pancreatic (PANC1) and prostate (DU145) cancer cells in which Hh signaling was activated. Compounds 4a and g had moderate selectivity against PANC1 cells. Western blotting analyses revealed that PTCH and GLI1 expression was reduced after treatment with these compounds. Overall, these synthetic flavonoids represent promising new additions to our expanding panel of Hh pathway inhibitors, and with further development these molecules may ultimately be considered for clinical use.

Original languageEnglish
Pages (from-to)784-795
Number of pages12
JournalChemical and Pharmaceutical Bulletin
Issue number8
Publication statusPublished - 2017
Externally publishedYes


  • Cytotoxicity
  • Hedgehog signaling
  • Inhibitor
  • Tandem reaction
  • flavonoid

ASJC Scopus subject areas

  • Chemistry(all)
  • Drug Discovery


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