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

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 and Guojian Zhang ()
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Hengyi Xu: Ocean University of China
Xianyan Zhang: Ocean University of China
Yawen Zhang: Ocean University of China
Guowei Liu: Ocean University of China
Yinghan Chen: Ocean University of China
Xuewen Hou: Ocean University of China
Xiaolin Liu: Ocean University of China
Kaijin Zhang: Ocean University of China
Chuanteng Ma: Ocean University of China
Ruqian Feng: Guangdong Pharmaceutical University
Juan Shen: Guangdong Pharmaceutical University
Blaine A. Pfeifer: The State University of New York
Qian Che: Ocean University of China
Tianjiao Zhu: Ocean University of China
Guojian Zhang: Ocean University of China

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62075-4

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