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14 pages, 3301 KB

Open AccessArticle

Targeted Dereplication of H. patulum and H. hookeranium Extracts: Establishing MS/MS Fingerprints for the Identification of Polycyclic Polyprenylated Acylphloroglucinols

by Annabelle Dugay, Florence Souquet, David Hozain, Gilles Alex Pakora, Didier Buisson, Séverine Amand, Marie-Christine Lallemand and Raimundo Gonçalves de Oliveira Junior

Molecules 2025, 30(12), 2531; https://doi.org/10.3390/molecules30122531 - 10 Jun 2025

Viewed by 1018

Abstract

In this study, we combined automated annotation tools with targeted dereplication based on MS/MS fragmentation pathway studies to identify polycyclic polyprenylated acylphloroglucinols (PPAPs) in Hypericum species, using H. patulum and H. hookeranium as a case study. These species, extensively used in traditional medicine, [...] Read more.

In this study, we combined automated annotation tools with targeted dereplication based on MS/MS fragmentation pathway studies to identify polycyclic polyprenylated acylphloroglucinols (PPAPs) in Hypericum species, using H. patulum and H. hookeranium as a case study. These species, extensively used in traditional medicine, exhibit morphological similarities that often result in misidentification. Following UHPLC-HRMS/MS analysis of plant extracts, a molecular network approach facilitated a comprehensive comparison of their chemical composition, assigning specific clusters to O-glycosylated flavonoids and PPAPs. Eight peaks, including quercitrin, isoquercitrin, procyanidins, chlorogenic acid, quercetin, and glycosylated derivatives, were annotated from the GNPS database. For PPAPs, despite the structural complexity posing challenges for automated annotation using public databases, our targeted-dereplication strategy, relying on in-house spectral data, led to the putative identification of 22 peaks for H. patulum and H. hookeranium. Key compounds such as hyperforin, hyperscabrone K, and garcinialliptone M were detected in both species, underscoring their chemical similarity. MS/MS fragmentation pathways, particularly the successive losses of isobutene and isoprenyl units, emerged as a consistent signature for PPAP detection and may be useful for selecting PPAP-enriched extracts or fractions for further phytochemical investigations. Full article

(This article belongs to the Special Issue The 30th Anniversary of Molecules—Recent Advances in Natural Products Chemistry)

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19 pages, 2024 KB

Open AccessArticle

Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53

by Aparna Viswanathan Ammanath, Miki Matsuo, Huanhuan Wang, Frank Kraus, Anton Bleisch, Philipp Peslalz, Majd Mohammad, Meghshree Deshmukh, Anne Grießhammer, Moushumi Purkayastha, Andreas Vorbach, Boris Macek, Heike Brötz-Oesterhelt, Lisa Maier, Dorothee Kretschmer, Andreas Peschel, Tao Jin, Bernd Plietker and Friedrich Götz

Int. J. Mol. Sci. 2024, 25(15), 8023; https://doi.org/10.3390/ijms25158023 - 23 Jul 2024

Cited by 1 | Viewed by 2735

Abstract

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John’s wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved [...] Read more.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John’s wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of −7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens. Full article

(This article belongs to the Special Issue Antibacterial and Antioxidant Effects of Plant-Sourced Compounds)

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9 pages, 1301 KB

Open AccessArticle

Hyperacmosin R, a New Decarbonyl Prenylphloroglucinol with Unusual Spiroketal Subunit from Hypericum acmosepalum

by Yonghui Ma, Xiaoyu Liu, Bo Liu, Pingping Li, Xinyue Suo, Tingting Zhu, Tengfei Ji, Jin Li and Xiaoxiu Li

Molecules 2022, 27(18), 5932; https://doi.org/10.3390/molecules27185932 - 13 Sep 2022

Cited by 3 | Viewed by 2080

Abstract

Two previously undescribed polycyclic polyprenylated acylphloroglucinols, hyperacmosins R-S (1–2), were obtained from the aerial parts of Hypericum acmosepalum. Their structures were elucidated by extensive spectroscopic analysis and electronic circular dichroism calculation (ECD). Compound 1 featured an unprecedented 5,8-spiroketal [...] Read more.

Two previously undescribed polycyclic polyprenylated acylphloroglucinols, hyperacmosins R-S (1–2), were obtained from the aerial parts of Hypericum acmosepalum. Their structures were elucidated by extensive spectroscopic analysis and electronic circular dichroism calculation (ECD). Compound 1 featured an unprecedented 5,8-spiroketal subunit as well as the loss of C-2′ carbonyl in the phloroglucinol ring. In addition, compounds 1 and 4 showed weak hepatoprotective activity against paracetamol-induced HepG2 cell damage at 10 μm. The plausible biosynthetic pathway of 1 was proposed via a retro-Clasisen reaction and decarboxylation. Full article

(This article belongs to the Section Natural Products Chemistry)

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3 pages, 635 KB

Open AccessCorrection

Correction: Wang et al. Polycyclic Polyprenylated Acylphloroglucinol Derivatives from Hypericum acmosepalum. Molecules 2019, 24, 50

by Jiao Wang, Mengjiao Shi, Jiajia Wang, Jin Li and Tengfei Ji

Molecules 2022, 27(13), 3986; https://doi.org/10.3390/molecules27133986 - 21 Jun 2022

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Abstract

The authors wish to make the following correction to their paper [...] Full article

(This article belongs to the Collection Bioactive Compounds)

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18 pages, 2726 KB

Open AccessArticle

Discovery of Novel Polycyclic Polyprenylated Acylphloroglucinols from the Fruits of Garcinia xanthochymus as Antitumor Agents by Suppressing the STAT3 Signaling

by Shan Jin, Wen Wang, Fei Gan, Wenli Xie, Jing Xu, Yu Chen, Zhinan Mei and Guangzhong Yang

Int. J. Mol. Sci. 2021, 22(19), 10365; https://doi.org/10.3390/ijms221910365 - 26 Sep 2021

Cited by 9 | Viewed by 2872

Abstract

Pharmacologic studies have revealed that polycyclic polyprenylated acylphloroglucinols (PPAPs) collectively exhibit a broad range of biological activities, including antineoplastic potential. Here, six new PPAPs, named garcixanthochymones F–K (3, 5, 7, 8, 11, and 15), together with [...] Read more.

Pharmacologic studies have revealed that polycyclic polyprenylated acylphloroglucinols (PPAPs) collectively exhibit a broad range of biological activities, including antineoplastic potential. Here, six new PPAPs, named garcixanthochymones F–K (3, 5, 7, 8, 11, and 15), together with nine known analogues were isolated from the fruits of Garcinia xanthochymus. Their structures were elucidated based on the spectroscopic data, including UV, HRESIMS, and NMR, and quantum chemical calculations. All the isolated PPAPs were tested for anti-proliferative activity against four human tumor cell lines, including SGC7901, A549, HepG2, and MCF-7. Most of the PPAPs possessed high anti-proliferative activity with IC₅₀ values in the range of 0.89 to 36.98 μM, and significant apoptosis was observed in MCF-7 cells exposed to compounds 2 and 5. Besides, docking results showed that compounds 2 and 5 could strongly combine with the Src homology 2 (SH2) domain of STAT3 via hydrogen bond and hydrophobic interaction, which is one of the key oncogenes and crucial therapeutic targets. Furthermore, compounds 2 and 5 efficiently downregulated the expression of p-STAT3^Tyr705 and pivotal effector proteins involved in oncogenic signaling pathways of MCF-7 cells. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Products for the Prevention and Treatment of Chronic Diseases)

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13 pages, 3327 KB

Open AccessArticle

A Photoalkylative Fluorogenic Probe of Guttiferone A for Live Cell Imaging and Proteome Labeling in Plasmodium falciparum

by Romain Duval, Kevin Cottet, Magali Blaud, Anaïs Merckx, Sandrine Houzé, Philippe Grellier, Marie-Christine Lallemand and Sylvie Michel

Molecules 2020, 25(21), 5139; https://doi.org/10.3390/molecules25215139 - 4 Nov 2020

Cited by 5 | Viewed by 3211

Abstract

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed [...] Read more.

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose–response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis. Full article

(This article belongs to the Special Issue Chemical Probe Synthesis and Applications in Chemical Biology)

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17 pages, 6885 KB

Open AccessArticle

Targeting MHC Regulation Using Polycyclic Polyprenylated Acylphloroglucinols Isolated from Garcinia bancana

by Chloé Coste, Nathalie Gérard, Chau Phi Dinh, Antoine Bruguière, Caroline Rouger, Sow Tein Leong, Khalijah Awang, Pascal Richomme, Séverine Derbré and Béatrice Charreau

Biomolecules 2020, 10(9), 1266; https://doi.org/10.3390/biom10091266 - 2 Sep 2020

Cited by 11 | Viewed by 3916

Abstract

Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory [...] Read more.

Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1–4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1–4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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14 pages, 2967 KB

Open AccessArticle

Hypermongone C Accelerates Wound Healing through the Modulation of Inflammatory Factors and Promotion of Fibroblast Migration

by Sara E. Moghadam, Mahdi Moridi Farimani, Sara Soroury, Samad N. Ebrahimi and Ehsan Jabbarzadeh

Molecules 2019, 24(10), 2022; https://doi.org/10.3390/molecules24102022 - 27 May 2019

Cited by 16 | Viewed by 4286

Abstract

The physiology of wound healing is dependent on the crosstalk between inflammatory mediators and cellular components of skin regeneration including fibroblasts and endothelial cells. Therefore, strategies to promote healing must regulate this crosstalk to achieve maximum efficacy. In light of the remarkable potential [...] Read more.

The physiology of wound healing is dependent on the crosstalk between inflammatory mediators and cellular components of skin regeneration including fibroblasts and endothelial cells. Therefore, strategies to promote healing must regulate this crosstalk to achieve maximum efficacy. In light of the remarkable potential of natural compounds to target multiple signaling mechanisms, this study aims to demonstrate the potential of hypermongone C, a polycyclic polyprenylated acylphloroglucinol (PPAP), to accelerate wound closure by concurrently enhancing fibroblast proliferation and migration, promoting angiogenesis, and suppressing pro-inflammatory cytokines. This compound belongs to a family of plants (Hypericum) that traditionally have been used to treat injuries. Nevertheless, the exact biological evidence to support the claims is still missing. The results were obtained using a traditional model of cell scratch assay and endothelial cell tube formation, combined with the analysis of protein and gene expression by macrophages. In summary, the data suggest that hypermongone C is a multi-targeting therapeutic natural compound for the promotion of tissue repair and the regulation of inflammation. Full article

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10 pages, 1289 KB

Open AccessArticle

Polycyclic Polyprenylated Acylphloroglucinol Derivatives from Hypericum acmosepalum

by Jiao Wang, Mengjiao Shi, Jiajia Wang, Jin Li and Tengfei Ji

Molecules 2019, 24(1), 50; https://doi.org/10.3390/molecules24010050 - 23 Dec 2018

Cited by 12 | Viewed by 4176 | Correction

Abstract

Hypericum acmosepalum belongs to the Hypericum genus of the Guttiferae family. The characteristic components in Hypericum are mainly a series of polycyclic polyprenylated acylphloroglucinols (PPAPs), flavonoids, and xanthones. Among them, the PPAPs have received much attention due to their novel structures and diverse [...] Read more.

Hypericum acmosepalum belongs to the Hypericum genus of the Guttiferae family. The characteristic components in Hypericum are mainly a series of polycyclic polyprenylated acylphloroglucinols (PPAPs), flavonoids, and xanthones. Among them, the PPAPs have received much attention due to their novel structures and diverse pharmacological activities and have become hot spots in organic chemistry and medicinal chemistry. However, there are few reports about the chemical constituents of Hypericum acmosepalum at present, especially the PPAPs. This research is dedicated to the study of the air-dried aerial parts of Hypericum acmosepalum, which were extracted with 95% EtOH under reflux, then suspended and successively partitioned with petroleum ether and ethyl acetate. Five PPAP derivatives were obtained using various chromatographic techniques, and their structures were determined by NMR spectroscopic data, including two new phloroglucinol derivatives, hyperacmosin A (1) and hyperacmosin B (2). Those compounds were evaluated for their neuroprotective effect using two models. Full article

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