Jietacins, azoxy natural products, as novel NF-κB inhibitors: Discovery, synthesis, biological activity, and mode of action

Mariko Watanabe, Akihiro Sugawara, Yoshihiko Noguchi, Tomoyasu Hirose, Satoshi Ōmura, Toshiaki Sunazuka, Ryouichi Horie

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Deregulation of NF-κB plays an important role in various diseases by controlling cell growth, inflammation, the immune response, and cytokine production. Although many NF-κB inhibitors have been developed, to the best of our knowledge, none of them have been successfully translated into clinical practice as medicines. To overcome this issue, we aimed to develop a new class of NF-κB inhibitors. Previous reports indicated that the N-terminal cysteine is a promising target for NF-κB. Based on this, we first selected 10 natural products or their derivatives from the natural product library that we developed and examined the effect on NF-κB and the viability of cancer cells with constitutively strong NF-κB activity. Among them, we found that an azoxy natural product, jietacin A, with a vinylazoxy group and an aliphatic side chain, reduced cell viability and inhibited nuclear translocation of free NF-κB. In addition, we performed design, synthesis, and biological evaluation of jietacin derivatives for development of a novel NF-κB inhibitor. Of these derivatives, a fully synthesized derivative 25 with vinylazoxy and ynone groups had a potent effect. We clarified the structure-activity relationship of this compound. Jietacin A and 25 also inhibited tumor necrosis factor-α-mediated induction of NF-κB. The NF-κB inhibitory effect depended on the N-terminal cysteine and the neighboring Arg-Ser-Ala-Gly-Ser-Ile (RSAGSI) domain of NF-κB. We also found that 25 inhibited the association between NF-κB and importin α, suggesting inhibition of NF-κB at an early step of nuclear translocation. Overall, this study indicated that the vinylazoxy motif may compose a new class of NF-κB inhibitors, providing further insight for rational drug design and rendering a unique mode of action.

Original languageEnglish
Pages (from-to)636-647
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2019 Sep 15


  • Cancer
  • Cysteine
  • Importin α
  • Jietacin
  • NF-κB inhibitor
  • Vinylazoxy
  • Ynone

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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