RRC ID 57814
著者 Watanabe M, Sugawara A, Noguchi Y, Hirose T, Ōmura S, Sunazuka T, Horie R.
タイトル Jietacins, azoxy natural products, as novel NF-κB inhibitors: Discovery, synthesis, biological activity, and mode of action.
ジャーナル Eur J Med Chem
Abstract 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.
巻・号 178
ページ 636-647
公開日 2019-9-15
DOI 10.1016/j.ejmech.2019.05.079
PII S0223-5234(19)30497-0
PMID 31226655
MeSH Azo Compounds / chemical synthesis Azo Compounds / chemistry Azo Compounds / pharmacology* Biological Products / chemical synthesis Biological Products / chemistry Biological Products / pharmacology* Cell Line, Tumor Cell Survival / drug effects Dose-Response Relationship, Drug Drug Discovery* Drug Evaluation, Preclinical Humans Molecular Structure NF-kappa B / antagonists & inhibitors* NF-kappa B / metabolism Structure-Activity Relationship
IF 5.573
引用数 0
リソース情報
ヒト・動物細胞 ATN-1(RCB1440)