Elsevier

Bioorganic Chemistry

Volume 105, December 2020, 104464
Bioorganic Chemistry

Macrocyclic diterpenoids from the seeds of Euphorbia peplus with potential activity in inducing lysosomal biogenesis

https://doi.org/10.1016/j.bioorg.2020.104464Get rights and content

Highlights

  • Five new diterpenoids were isolated from the seeds of Euphorbia peplus.

  • Compounds 13 feature a very rare euphoperfoliane 5/11/5-tricyclic skeleton.

  • Compounds 1 & 3 can significantly induce lysosomal biogenesis by activation of TFEB.

Abstract

The first phytochemical investigation of the seeds of Euphorbia peplus led to the isolation and characterization of five new (15), named euphopepluanones A–E, and five known diterpenoids (610). Their structures were established by extensive spectroscopic analysis and X-ray crystallographic experiments. Euphopepluanones A–E (13) feature a very rare 5/11/5-tricyclic skeleton, and euphopepluanones D–E (45) represent the first report of lathyrane type diterpenoids found in E. peplus. The new compounds 15 were assessed for their activities to induce lysosomal biogenesis through LysoTracker Red staining, in which compounds 1 and 3 could significantly induce lysosomal biogenesis. In addition, compounds 1 and 3 could promote the nuclear translocation of TFEB, a master transcriptional factor of lysosomal genes, indicating that compounds 1 and 3 induced lysosomal biogenesis through activation of TFEB.

Introduction

The genus Euphorbia is the third largest genus in flowering plants, comprising almost 2000 species [1]. Plants of Euphorbia are a rich source of structurally diverse polycyclic, especially macrocyclic, diterpenoids possessing great skeletons diversity and the wide range of therapeutically relevant biological activities including antitumor, cytotoxic, multi-drug-resistance-reversing, anti-viral properties, and anti-inflammatory activity [2]. Euphorbia peplus Linn. is a small annual weed indigenous to Europe and North Africa, and was introduced into Yunan province of China [3]. Several decades phytochemical investigations have mostly focused on the diterpenoids of the whole plant of E. peplus, which have yielded a series of diterpenoids with jatrophane, ingenane, pepluane, paraliane, segetane skeletons [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. Notably, ingenol 3-angelate isolated from E. peplus was approved by the FDA in 2012 for the treatment of actinic keratosis, a precancerous skin condition [16], [17].

Previously, our group has found that analogues of ingenol 20-deoxygenol could induce lysosomal biogenesis. In vivo studies have shown that these compounds can clear amyloid-β in the brain of mice, suggesting that these compounds have the potential to be developed for the treatment of neurodegenerative diseases [18]. To identify more diterpenes which could induce lysosomal biogenesis from E. peplus, we studied the chemical composition of the seeds of E. peplus, which was not investigated previously. Five undescribed diterpenoids (euphopepluanones A–E, 15) were obtained, including very rare euphoperfoliane type diterpenes euphopepluanones A–C (13), and euphopepluanones D–E (45) representing the first report of lathyrane type diterpenoids in the species, along with five known diterpenoids (Fig. 1). In addition, the lysosomal biogenesis activities of compounds 15 were evaluated through LysoTracker Red staining. Herein, we describe the isolation, structural determination and biological evaluation of these compounds.

Section snippets

General experimental procedures

Optical rotation measurements were conducted with a Jasco P-1020 automatic polarimeter. ECD spectra were determined on the Applied Photophysics circular dichroism spectrometer (Applied Photophysics, Leatherhead, Surrey, UK). IR spectra were recorded on a NICOLET iS107 Mid-infrared spectrometer. NMR spectra were measured on Bruker AVANCE III 500 MHz and AV 600 MHz NMR spectrometers with TMS as the internal standard. High-resolution MS data were performed on an Agilent 1290 UPLC/6540 Q-TOF mass

Structural elucidation of isolated compounds

Compound 1 was obtained as colorless prism crystals. The molecular formula was determined to be C29H34O8 based on its positive HRESIMS ([M+Na]+, m/z 533.2145, calcd for C29H34O8Na, 533.2146), corresponding to 13 degrees of unsaturation. The IR spectrum showed absorption bands assignable to hydroxyl (3447 cm−1), carbonyl (1741 and 1715 cm −1), and aromatic ring (1557 and 1453 cm−1) functionalities. The 1H, 13C NMR and DEPT spectra of 1 showed 29 carbon signals (Table 1), including typical

Conclusion

In summary, for the first time, the chemical profile of the seeds of E. peplus was investigated to afford euphopepluanones A–C (13) featuring rare 5/11/5-tricyclic skeleton, and euphopepluanones D–E (45) the first lathyrane type diterpenoids found in E. peplus, which were distinct to that of the whole plants. Compounds 1 and 3 could significantly induce lysosomal biogenesis through activation of TFEB, a master transcriptional factor of lysosomal genes.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This research was supported by the National Key R&D Program of China under Grant (number 2018YFA0900600); Open Fund of Shanghai Key Laboratory of Plant Functional Genomics and Resources under Grant (number PFGR201902); Technological leading talent project of Yunnan (2015HA020); National Natural Science Foundation of China under Grant (numbers 21432010; 31872666; 81703393); Special Fund for Talent Introduction of Kunming Institute of Botany, CAS (to Xin Fang); and Key R&D Program of Yunnan under

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      Euphorblin B (179), euphorblin D (181) and compound (560) showed remarkable immunofluorescence strength, and their Lyso Tracker staining intensities were 155.9%, 143.5% and 132.6%, separately (Chen et al., 2021b; Zhao et al., 2018). Euphopepluanone A (609), euphopepluanone C (611) and euphopepluanones F–K (455–458, 524 and 520) could significantly induce lysosomal biogenesis through Lyso Tracker Red staining (Chen et al., 2020). Euphopepluanone G (456) signifcantly induced lysosomal biogenesis and could increase the number of LC3 dots, indicating that it could activate the lysosomal-autophagy pathway (Chen et al., 2021a).

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    These authors contributed equally to this work.

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