Macrocyclic diterpenoids from the seeds of Euphorbia peplus with potential activity in inducing lysosomal biogenesis
Graphical abstract
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, 1–5) were obtained, including very rare euphoperfoliane type diterpenes euphopepluanones A–C (1–3), and euphopepluanones D–E (4–5) 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 1–5 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 (1–3) featuring rare 5/11/5-tricyclic skeleton, and euphopepluanones D–E (4–5) 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
References (28)
- et al.
Global medicinal uses of Euphorbia L. (Euphorbiaceae)
J. Ethnopharmacol.
(2015) - et al.
Biologically active diterpene esters from Euphorbia peplus
Phytochemistry
(1985) - et al.
Diterpenes from Euphorbia peplus
Phytochemistry
(1998) - et al.
Jatrophane diterpenoids from Euphorbia peplus
Phytochemistry
(1999) - et al.
A new jatrophane diterpenoid from Euphorbia peplus
Chin. J. Nat. Med.
(2010) - et al.
One-Step Semisynthesis of a Segetane Diterpenoid from a Jatrophane Precursor via a Diels-Alder Reaction
Org. Lett.
(2016) - et al.
Three Minor Diterpenoids with Three Carbon Skeletons from Euphorbia peplus
Org. Lett.
(2016) - et al.
Chemical profile and defensive function of the latex of Euphorbia peplus
Phytochemistry
(2017) - et al.
Pepluanols C-D, Two Diterpenoids with Two Skeletons from Euphorbia peplus
Org. Lett.
(2018) - et al.
Diterpenes and phloracetophenones from Euphorbia portulacoides
Phytochemistry
(1996)
Diterpenes from Euphorbia paralias
Phytochemistry
Euphorbia diterpenes: isolation, structure, biological activity, and synthesis (2008–2012)
Chem. Rev.
Isolation and structure revision of pepluane diterpenoids from Euphorbia peplus
J. Nat. Prod.
Cited by (13)
Diterpenoids from Euphorbia peplus possessing cytotoxic and anti-inflammatory activities
2024, Bioorganic ChemistryDiterpenoids from Euphorbia lactea and their anti-HIV-1 activity
2023, PhytochemistryEuphpepluone S, a new lathyrane diterpenoid with anti-inflammatory activity from Euphorbia peplus L.
2023, Phytochemistry LettersPhytochemical and pharmacological review of diterpenoids from the genus Euphorbia Linn (2012–2021)
2022, Journal of EthnopharmacologyCitation Excerpt :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).
Euphorbia diterpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013-2021)
2022, Natural Product Reports
- 1
These authors contributed equally to this work.