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<p>The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecular oxa/aza-nucleophilic addition in the biosynthesis of a family of eremophilane-like sesquiterpenoid derivatives, including farfugin A (<b>1</b>) and aza-janthinellin A (<b>2a</b>), a sesquiterpene-amino acid adduct. During this process, JanF, a flavoprotein functioning as a dehydrogenase, is demonstrated to be able to oxidize an allyl alcohol group of eremophilanes into an α,β-unsaturated aldehyde, thereby facilitating the binding of primary amines to the sesquiterpene skeleton. Furthermore, using JanF as a catalyst, we generate a series of aromatic aza-/thio-sesquiterpenoids (aza-janthinellins and thio-janthinellins), among which, thio-janthinellins exhibit potent cytotoxicity against human chronic myelogenous leukemia K562 cells. These findings advance our understanding of the biogenesis of aromatic compounds and enable the construction of diverse aza-/thio-terpenoids with enhanced biological activity.</p>

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Nucleophilic addition promoted ring rearrangement-aromatization in aza-/thio-sesquiterpenoid biosynthesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月9日

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  • Hengyi Xu,
  • Xianyan Zhang,
  • Yawen Zhang,
  • Guowei Liu,
  • Yinghan Chen,
  • Xuewen Hou,
  • Xiaolin Liu,
  • Kaijin Zhang,
  • Chuanteng Ma,
  • Ruqian Feng,
  • Juan Shen,
  • Blaine A. Pfeifer,
  • Qian Che,
  • Tianjiao Zhu,
  • Guojian Zhang

摘要

The aromatization of terpenoid scaffold has received enduring attention as it introduces diverse structural alterations and endows bioactivity to the molecules. In this study, we discover a unique aromatization mechanism involving consecutive [1,2]-alkyl migrations initiated by intramolecular oxa/aza-nucleophilic addition in the biosynthesis of a family of eremophilane-like sesquiterpenoid derivatives, including farfugin A (1) and aza-janthinellin A (2a), a sesquiterpene-amino acid adduct. During this process, JanF, a flavoprotein functioning as a dehydrogenase, is demonstrated to be able to oxidize an allyl alcohol group of eremophilanes into an α,β-unsaturated aldehyde, thereby facilitating the binding of primary amines to the sesquiterpene skeleton. Furthermore, using JanF as a catalyst, we generate a series of aromatic aza-/thio-sesquiterpenoids (aza-janthinellins and thio-janthinellins), among which, thio-janthinellins exhibit potent cytotoxicity against human chronic myelogenous leukemia K562 cells. These findings advance our understanding of the biogenesis of aromatic compounds and enable the construction of diverse aza-/thio-terpenoids with enhanced biological activity.