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. 2019 Aug 13:15:1933-1944.
doi: 10.3762/bjoc.15.189. eCollection 2019.

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

Affiliations

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

Silvie Rimpelová et al. Beilstein J Org Chem. .

Abstract

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

Keywords: anti-inflammatory properties; archangelolide; dansyl fluorescent conjugate; sarco/endoplasmic reticulum calcium ATPase; sesquiterpene lactone; trilobolide analogue.

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Figures

Figure 1
Figure 1
The structure of the sesquiterpene lactones archangelolide (1) and trilobolide (2).
Scheme 1
Scheme 1
Reagents and conditions: a) MeOH, TEA, 48 h, yield 32%; b) (i) 5-azidopentanoic acid, DCC, DCM, 90 min, rt; (ii) 4-DMAP, DCM, 8 h, rt, 86%; c) dansylated propargylamine, CuI, TBTA, THF, MW, 70 °C, 2 h, yield 64%.
Figure 2
Figure 2
Intracellular localization of archangelolide-dansyl (5) in human cells from osteosarcoma (U-2 OS). A, C) Bright-field images; B, D) fluorescence microscopy of living cells treated with 1 µM concentration of compound 5 for 90 min.
Figure 3
Figure 3
Co-localization of dansylarchangelolide 5 with a marker of endoplasmic reticulum (top row) and with a mitochondrial marker (bottom row) in human cells from osteosarcoma (U-2 OS). A, E) Bright-field images. Fluorescence microscopy of living cells treated with 1 µM concentration of compound 5 (90 min; images B and F) and a mitochondria-specific dye from [20] (10 min; image C) or pDNA coding mCherry-ER (image G). D, H) merged images.
Figure 4
Figure 4
Cartoon representation of sarco/endoplasmic reticulum Ca2+ ATPase binding pocket with A, C) archangelolide (1) or B, D) trilobolide (2) after molecular dynamic simulations. Depicted are also amino acid residues in a range of 5 Å from the respective ligand. The images were created using VMD software, version 1.9.2.
Figure 5
Figure 5
Molecular surface representation of sarco/endoplasmic reticulum Ca2+ ATPase binding pocket with A) archangelolide (1) and B) trilobolide (2) after molecular dynamic simulations. SURF function and probe size 1.4 Å were used. SURF function was written by Amitabh Varshney in University of North Carolina. The images were created using VMD software, version 1.9.2.
Figure 6
Figure 6
Structural formulae of (i) thapsigargin, (ii) trilobolide (2), and (iii) archangelolide (1). Red parts show structural moieties of thapsigargin and its derivatives contributing to SERCA binding affinity (according to [22]): A) octanoyl, B) butanoyl or 2-methylbutanoyl, C) acetyl, D) angeloyl.
Figure 7
Figure 7
Viability of rat peritoneal cells treated with archangelolide (1), dansylarchangelolide 5 and dansyl amide itself. Compounds were applied at 4 µM and 40 µM concentrations and cells were cultured for 24 h. WST-1 assay was used for viability evaluation. The results are expressed as percentage of untreated control ± SEM of n = 6–8 values from two independent experiments. Statistical significance: *P < 0.05, the results of compound 5 are statistically different from those of untreated cells.
Figure 8
Figure 8
NO production in primary rat macrophages. The cells were treated with archangelolide (1) and dansylarchangelolide 5 in the concentration range of 0.1–40 µM for 24 h with or without lipopolysaccharide (LPS, 1000 pg·mL−1) or with solely 40 µM dansyl amide. The results represent the mean ± SEM of three independent experiments, n = 6. Statistical significance: * P < 0.01, **P < 0.001, the results of the compounds are statistically different from those of the LPS-treated cells.
Figure 9
Figure 9
Evaluation of cytokine TNF-α secretion in rat peritoneal cells. Stimulation of primary cells was induced by 1000 pg·mL−1 of LPS. Cells were cultured in the presence of archangelolide (1) and dansylarchangelolide 5 for 24 h. Cytokine secretion was detected by ELISA. The data are the means ± SEM of two independent experiments, n = 4.
Figure 10
Figure 10
Structure of laserolide.

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