Polycyclic polyprenylated acylphloroglucinols with immunosuppressive activity from Hypericum perforatum and absolute configurations assignment of previously reported analogues

doi:10.1016/j.bioorg.2021.105144

Bioorganic Chemistry

Volume 114, September 2021, 105144

https://doi.org/10.1016/j.bioorg.2021.105144 Get rights and content

Highlights

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Thirteen undescribed PPAPs were isolated from Hypericum perforatum.
•
Absolute configurations of four previously reported PPAPs were assigned for the first time.
•
Compounds 1, 3, 4, 5, 7, and 11 showed immunosuppressive activity with IC₅₀ values ranging from 4.1 to 9.7 μM.
•
Compounds 1, 12, and 13 exerted neuroprotective activity under the concentration of 10 μM.

Abstract

Hyperformitins A–I (1–9), nine undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) with double-bond migration, along with four new isomers hyperformitins J–M (10–13), were isolated from Hypericum perforatum. Their structures and absolute configurations were determined by spectroscopic analyses including HRESIMS, IR, UV, NMR, and ECD, as well as optical rotation (OR) calculations. The absolute configurations of previously reported analogues, garsubellins D and C as well as garcinielliptones L and M, were assigned for the first time by NMR spectra and specific rotations analyses assisting with OR calculations. Selected compounds were tested for their immunosuppressive activities against lipopolysaccharide (LPS)-induced B lymphocyte proliferation. Compounds 1, 3, 4, 5, 7, and 11 showed inhibition activities against the proliferation of B lymphocyte with IC₅₀ values ranging from 4.1 to 9.7 μM. Furthermore, the neuroprotective activities of the isolates against corticosterone (CORT)-induced injury in PC12 cells were also tested, and compounds 1, 12, and 13 exhibited neuroprotective effects with cell viabilities of 68.0%, 71.3%, and 68.4%, respectively under the concentration of 10 μM.

Graphical abstract

Introduction

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a group of acylphloroglucinol derivatives featured by highly oxygenated acylphloroglucinol cores, which were densely decorated with isoprenyl or geranyl moieties [1], [2]. Since the first PPAP has been isolated from Hypericum perforatum L. (St. John’s wort) in 1971 [3], [4], this class of natural products have been extensively investigated because of their intricate molecular structures [5], [6], [7], [8], [9] and diverse biological activities [10], [11], [12], [13]. As the most famous medicinal herb from the genus of Hypericum, St. John’s wort has been used to treat depression in Europe for a long time due to its potent antidepressive activity on mild-moderate depression [14], [15], [16], [17], [18]. In recent years, St. John’s wort has also attracted broad interest for its pharmacological activities on neurological and immunological diseases [19], [20], [21].

Previous phytochemical investigations on H. perforatum by our group demonstrated that this plant is also a rich source of PPAPs [22], [23]. PPAPs are usually obtained as oils or gums, which were difficult to determine their absolute configurations by single-crystal method. In this study, thirteen undescribed PPAPs (1–13) were isolated from H. perforatum (Fig. 1) and their structures and absolute configurations were determined by extensive spectroscopic analyses. Furthermore, the absolute configurations of four previously reported analogues, garsubellins D and C [24] as well as garcinielliptones L and M [25], were assigned for the first time by NMR spectra analyses and OR calculations. The immunosuppressive activities and neuroprotective activities of selected compounds were also reported.

Section snippets

General

Optical rotations were determined by a PerkinElmer 341 polarimeter (PerkinElmer Inc., Fremont, California, USA). UV spectra were recorded on a Lambda 35 instrument (PerkinElmer Inc., Fremont, California, USA). ECD spectra were determined on a JASCO-810 spectrometer (JASCO, Tokyo, Japan). IR spectra were obtained using a Bruker Vertex 70 FT-IR spectrophotometer (Bruker, Karlsruhe, Germany). The NMR spectra were acquired on Bruker AM-400, AV-600, and AV-800 spectrometers, and the ¹H and ¹³C NMR

Structure elucidation

Hyperformitin A (1) had the molecular formula of C₃₅H₅₂O₆ based on its ¹³C NMR data and HRESIMS [M+Na]⁺ ion at m/z 591.3656 (calcd for 591.3656). The absorption bands of the IR spectrum exhibited the presence of hydroxy (3436 cm⁻¹) and carbonyl (1722 cm⁻¹) functionalities. The ¹H NMR data (Table 2) showed signals of nine methyl singlets (δ_H 1.06–1.68, s), an isopropyl group (δ_H 1.13, d; 1.06, d; 2.64, sept), and four olefinic protons (δ_H 4.96–5.66). Analyses of the ¹³C and DEPT NMR data (Table 1

Conclusions

In summary, thirteen undescribed PPAPs (1–13) were isolated from Hypericum perforatum. Hyperformitins A–I (1–9) were featured by double-bond migration on the isoprenyl side chain. Their structures and absolute configurations were established by spectroscopic methods and the ECD spectra analysis. The absolute configurations of garsubellins D and C as well as garcinielliptones L and M were assigned for the first time by NMR spectra and specific rotations analyses together with OR calculations.

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.

Acknowledgments

This work was financially supported by the Program for Changjiang Scholars of the Ministry of Education of the People's Republic of China (No. T2016088), the National Natural Science Foundation for Distinguished Young Scholars (No. 81725021), the National Natural Science Foundation for Excellent Young Scholars (81922065), the Innovative Research Groups of the National Natural Science Foundation of China (No. 81721005), the National Natural Science Foundation of China (No. 21502057), the

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Hyperatins A–D (1–4), four previously undescribed polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum perforatum L. (St. John's wort). Compound 1 possessed a unique octahydroindeno[1,7a-b]oxirene ring system with a rare 2,7-dioxabicyclo[2.2.1]heptane fragment. Compounds 2–4 had an uncommon decahydrospiro[furan-3,7′-indeno[7,1-bc]furan] ring system. Their structures were established by spectroscopic analyses and X-ray crystallography. Plausible biosynthetic pathways of 1–4 were also proposed. Compounds 1 and 2 exerted promising hypoglycemic activity by inhibiting glycogen synthase kinase 3 expression in liver cells.
Discovery of bioactive polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons from Hypericum wilsonii
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In this work, nine previous undescribed polycyclic polyprenylated acylphloroglucinols with adamantine/homoadamantane skeletons, cumilcinols A−I (1−9), along with six known analogues, were isolated and identified from the stems, leaves and flowers of Hypericum wilsonii. Their structures were determined by HRESIMS, NMR spectroscopic analysis, single-crystal X-ray crystallography as well as electronic circular dichroism calculations and comparisons. Compound 2 formed a unique furan ring bearing a rare acetal functionality. In bioassays, hyperacmosin G (13) could significantly inhibit the production of NO in LPS-stimulated RAW264.7 cell (IC₅₀ = 4.350 ± 1.146 μM), and increased expression of related transcription factors at the gene level, inhibit the nuclear translocation of NF-κBp65, and reduce the protein expression of COX-2. Additionally, compound 5 showed significant inhibitory activity on Con A-induced T-lymphocyte proliferation (IC₅₀ = 4.803 ± 3.149 μM), and treatment of 5 could reduce the increased ratio of CD4 and CD8 subpopulations induced by Con A in vitro. Those results indicated 13 possesses potential anti-inflammatory activity, and 5 exhibits a certain degree of immunosuppressive activity.
Hyperipersions A-C, three new acylphloroglucinols from the branches and leaves of Hypericum perforatum L. with antiangiogenic activities
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Three new acylphloroglucinols were isolated from the branches and leaves of Hypericum perforatum L., named as hyperipersions A-C (1-3), together with three known compounds which were identified as elegaphenone (4), 2,6-dihydroxy-3,4-dimethylbenzoic acid methyl ester (5) and 2,3-methylenedioxyxanthone (6), respectively. The structures of isolated compounds were determined by UV, IR, HR-ESI-MS, NMR analysis. Their antiangiogenic activities were studied against HUVECs. The IC₅₀ value of compound 3 was 2.39 ± 0.21 μM against HUVECs, which was stronger than vatalanib, and other compounds had moderate antiangiogenic activity.
Discovery of bicyclic polyprenylated acylphloroglucinols from Hypericum himalaicum with glucose transporter 4 translocation activity
2022, Bioorganic Chemistry
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The divergence between the planar structure of 15 and 13 was the situation of the furan ring. At the same time, the comparison of 15 with hyperformitin M in the literature [32] also showed that the position of the furan ring was different from compound 13. The HMBC interactions (Fig. 3) from H2-8 to C-2 (δC 190.8) as well as the difference of chemical shift at C-7 (δC 73.7) suggested the furan moiety was formed with C-3 and C-4.
Hyperhimatins A-P (1–16), sixteen new bicyclic polyprenylated acylphloroglucinols (BPAPs), were isolated and identified from Hypericum himalaicum. The planner structures of hyperhimatins A-P were confirmed via extensive NMR and careful HRESIMS data analysis. The absolute configurations of the new compounds were mainly determined by electronic circular dichroism (ECD) calculation, NMR calculation, and the circular dichroism data of the in situ formed [Rh₂(OCOCF₃)₄] complexes. All compounds were assessed for the glucose transporter 4 (GLUT-4) translocation and expression enhancing effects in L6 myotubes. Compounds 1–16 could promote the GLUT-4 expression by the range of 1.95–6.04 folds, and accelerate the GLUT-4 fusion with the plasma membrane ranged from 53.56% to 76.97% at a consistence of 30 μg/mL, among compound 10 displayed the strongest GLUT-4 translocation effect.
(±)-Hyperpyran A: Terpenoid-based bicyclic dihydropyran enantiomers with hypoglycemic activity from Hypericum perforatum (St. John's wort)
2022, Fitoterapia
Citation Excerpt :
Therefore, PPAPs have attracted considerable attention from chemists and pharmacologists over the past decades, while few studies have been performed on other phytochemicals of the genus Hypericum [7,8]. During the investigation of structurally intriguing and biologically active constituents from H. perforatum, a variety of new PPAPs were reported by our group [9–14]. However, in addition to the main components, PPAPs, there were still a few other interesting chemical components that were found.
(±)-Hyperpyran A (1a/1b), a pair of new terpenoid-based bicyclic dihydropyran enantiomers, were isolated from the aerial parts of Hypericum perforatum (St. John's wort). Their structures and absolute configurations were elucidated by NMR spectroscopic analyses, ECD comparison, and X-ray crystal diffraction. Compounds 1a/1b possess hexahydrocyclopenta[c]pyran ring system and a plausible biosynthetic pathway was also proposed. In addition, compound 1a exhibited a moderate promotion of glucose uptake activity in hepatocytes.
Discovery of Undescribed Monoterpenoid Polyprenylated Acylphloroglucinols with Immunosuppressive Activities from Hypericum longistylum
2022, Phytochemistry
Citation Excerpt :
Therefore, it is urgent to find more effective immunosuppressive agents in natural products. Currently, different types of PPAPs have been reported in these studies (Guo et al., 2021; Xie et al., 2021; Duan et al., 2021), apart from monoterpenoid polyprenylated acylphloroglucinols. Subsequently, compounds 1–7 were tested for their immunosuppressive activity in anti-CD3/anti-CD28 mAbs, LPS and Con A induced murine splenocyte proliferation.
Acylphlorostylums A–G (1–7), seven undescribed monoterpenoid polyprenylated acylphloroglucinols, were isolated and identified from Hypericum longistylum. Significantly, acylphlorostylums A and B were the first monoterpenoid polyprenylated acylphloroglucinols possessing a dodecahydro-1H-benzo [b]cyclopenta [e]oxepine moiety bearing a 6/7/5 fused tricyclic ring system that assembled by the attack from 4-OH to C-13. In addition, acylphlorostylums A–G exhibited moderate in vitro immunosuppressive activity in anti-CD3/anti-CD28 monoclonal antibodies, lipopolysaccharide and concanavalin A-induced murine splenocyte proliferation, with IC₅₀ values ranging from 1.51 ± 0.12 to 18.49 ± 1.67 μM, underscoring those isolates as novel chemical templates in the development of novel immunosuppressors.

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Polycyclic polyprenylated acylphloroglucinols with immunosuppressive activity from Hypericum perforatum and absolute configurations assignment of previously reported analogues

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

General

Structure elucidation

Conclusions

Declaration of Competing Interest

Acknowledgments

Tetrahedron Lett.

Org. Lett.

Neuropsychopharmacology.

Lancet.

Life Sci.

Trends Pharmacol. Sci.

J. Affect. Disord.

Org. Biomol. Chem.

Phytochemistry.

Org. Lett.

Phloroglucinol compounds of natural origin

Nat. Prod. Rep.

Research progress of polycyclic polyprenylated acylphloroglucinols

Chem. Rev.

Antibiotic hyperforin from Hypericum perforatum L

Antibiotiki

Catalytic asymmetric total synthesis of ent -hyperforin

Angew. Chem. Int. Ed.

Enantioselective total synthesis of hyperforin

J. Am. Chem. Soc.

The total synthesis of hyperforin

J. Am. Chem. Soc.

Bioactive acylphloroglucinols with adamantyl skeleton from hypericum sampsonii

Org. Lett.

Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John’s wort that acts by induction of apoptosis

Oncogene