Hyperatins A-D, highly oxidized polycyclic polyprenylated acylphloroglucinols from Hypericum perforatum L. with hypoglycemic potential in liver cells.

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.

Meroterpenes and prenylated benzoylphloroglucinol from the flowers of Hypericum formosanum.

Formohyperins A-F, previously undescribed meroterpenes, and grandone, a prenylated benzoylphloroglucinol being considered to be one of their biogenetic precursors, were isolated from the flowers of a Hypericaceous plant, Hypericum formosanum Maxim. Detailed spectroscopic analyses showed that formohyperins A-D were meroterpenes with an enolized 3-phenylpropane-1,3-dione moiety. Formohyperins E and F were elucidated as meroterpenes having a 4-benzoyl-5-hydroxycyclopent-4-ene-1,3-dione moiety. Formohyperins A-C and E were optically active, and their absolute configurations were deduced by comparison of the experimental and TDDFT calculated ECD spectra. In contrast, formohyperin D was concluded to be a racemate. Formohyperins A-F and grandone were found to show inhibitory activities against LPS-stimulated IL-1ß production from murine microglial cells with EC50 values of 13.2, 6.6, 8.5, 24.3, 4.1, 10.9, and 3.0 µM, respectively.

Two rearranged acylphloroglucinols with moderate neuroprotective effects from Hypericum ascyron Linn.

Phytochemical studies on the leaves and twigs of Hypericum ascyron Linn. led to the isolation of two previously undescribed rearranged polycyclic polyprenylated acylphloroglucinols (PPAP) with a 4,5-seco-3(2H)-furanone skeleton, named hyperascone A and B (1-2). Additionally, a known PPAP tomoeone A (3) and two known xanthones 1,3,5 -trihydroxy-6-O-prenylxanthone (4) and 3,7-dihydroxy-1,6-dimethoxyxanthone (5) were also isolated. The structures of the compounds were determined by the analysis of their spectroscopic data including HRMS, NMR and ECD. All of the five isolated compounds exhibited neuroprotective effects against MPP+ and microglia activation induced damage of SH-SY5Y cells.

Formyl phloroglucinol meroterpenoids from the leaves of Eucalyptus globulus subsp. maidenii and their ATP-citrate lyase inhibitory activities.

Three new formyl phloroglucinol meroterpenoids, eumaidials A-C (1-3), were isolated from the leaves of Eucalyptus globulus subsp. maidenii, along with ten known analogues (4-13). Their chemical structures were determined by various spectral data and electronic circular dichroism calculations. Eumaidial A (1) is the first ß-caryophyllene-based formyl phloroglucinol meroterpenoids from the genus Eucalyptus. Compounds 1-4 and 10 exhibited ATP-citrate lyase inhibitory activities, and compounds 2 and 3 suppressed the hepatocyte lipogenesis.

Lysidrhodosides A-I, acylphloroglucinol glucosides with anti-inflammatory activities from the leaves of Lysidice rhodostegia.

Lysidrhodosides A-I (1-9), nine acylphloroglucinol glucoside derivatives along with three known analogues (10-12) were isolated from the leaves of Lysidice rhodostegia. Their structures and absolute configuration were elucidated by spectroscopic data analysis (NMR, UV, IR, HR-ESI-MS), single-crystal X-ray diffraction, and acid hydrolysis with HPLC analysis. Notably, compounds 7-9 represent the first examples of 3-methylbutyryl phloroglucinol glucoside dimers isolated from this plant. Additionally, compounds 1-12 were assessed for their inhibitory effects on nitric oxide (NO) in the LPS-induced BV-2 cells. The results showed that compounds 6 and 12 significantly inhibited the production of the inflammatory mediator NO, with an inhibitory rate of 95.96 and 91.13% at a concentration of 50 µM, respectively.

Rearranged Homoadamantane-Type Polycyclic Polyprenylated Acylphloroglucinols from Hypericum pseudohenryi.

Hypseudohenones A-C (1-3), the first rearranged homoadamantane-type polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum pseudohenryi. Their structures with an unprecedented tricyclo[4.3.1.13,8]undecane-2,4,10-trione core were determined by spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A method for determining the relative configuration at C-3 was established by the peak shape of H-28 or J-value of H-3/H-28. Moreover, 2-3 exhibited significant AChE inhibitory activity, and the interactions of 2-3 with AChE were evaluated by molecular docking.

Structure Revision of Type B Polycyclic Polyprenylated Acylphloroglucinols Fused to a Partly Reduced Furan Ring.

Four previous papers reported the isolation and structural determination of 10 polycyclic polyprenylated acylphloroglucinols (PPAPs), uraliones F, G, K, and O, attenuatumiones E and F, and scabrumiones A-D, from Hypericum species. Their structures were identified as type B PPAPs that featured not only the characteristic acyl group at C-3 of the bicyclo[3.3.1]nonane core but also a partly reduced furan ring fused to the C-1-C-2-O-2 atoms of the core. However, the 1D and 2D NMR data of these compounds were more consistent with type A PPAPs that featured not only the acyl group at C-1 but also a partially reduced furan ring fused to the C-3-C-2-O-2 atoms of the core. Now we revise these 10 previously proposed structures to the corresponding type A PPAPs via NMR analysis. Additionally, we propose a rule that uses NMR data to determine whether a particular PPAP that is fused to a partly reduced furan ring at C-3-C-2-O-2 or C-1-C-2-O-2 is type A or type B, respectively. We also propose a rule to assign the relative configurations of corresponding type A PPAPs at C-18 and revise the configurations of sampsonione N, hypericumoxides A-C, and hyperscabin G.

Oligomeric phloroglucinols with hAChE inhibitory and antibacterial activities from tropic Rhodomyrtus tomentosa.

Alzheimer's diseases (AD) and other infectious diseases caused by drug-resistance bacteria have posed a serious threat to human lives and global health. With the aim to search for human acetylcholinesterase (hAChE) inhibitors and antibacterial agents from medicinal plants, 16 phloroglucinol oligomers, including two new phloroglucinol monomers (1a and 1b), four new phloroglucinol dimers (3a, 3b, 4b, and 5a), six new phloroglucinol trimers (6a, 6b, 7a, 7b, 8a, and 8b), and two naturally occurring phloroglucinol monomers (2a and 2b), along with two known congeners (4a and 5b), were purified from the leaves of tropic Rhodomyrtus tomentosa. The structures and absolute configurations of these new isolates were unequivocally established by comprehensive analyses of their spectroscopic data (NMR and HRESIMS), ECD calculation, and single crystal X-ray diffraction. Structurally, 3a/3b shared a rare C-5' formyl group, whereas 6a/6b possessed a unique C-7' aromatic ring. In addition, 7a/7b and 8a/8b were rare phloroglucinol trimers with a bis-furan and a C-6' hemiketal group. Pharmacologically, the mixture of 3a and 3b showed the most potent human acetylcholinesterase (hAChE) inhibitory activity with an IC50 value of 1.21 ± 0.16 µM. The molecular docking studies of 3a and 3b in the hAChE binding sites were performed, displaying good agreement with the in vitro inhibitory effects. In addition, the mixture of 3a and 3b displayed the most significant anti-MRSA (methicillin-resistant Staphylococcus aureus) with MIC and MBC values of both 0.50 µg/mL, and scanning electron microscope (SEM) studies revealed that they could destroy the biofilm structures of MRSA. The findings provide potential candidates for the further development of anti-AD and anti-bacterial agents.

Polycyclic polyprenylated acylphloroglucinols from Hypericum sampsonii Hance and their anti-inflammatory activity.

Phytochemical investigation of Hypericum sampsonii Hance resulted in the isolation of thirty-five polycyclic polyprenylated acylphloroglucinols including six new ones (1, 3, 5, and 15-17). Their structures were elucidated by UV, IR, NMR, HRESIMS, and calculated ECD analysis. Some compounds were evaluated for their anti-inflammatory effects in LPS-induced RAW264.7 cells. Compounds 1 and 26 showed significant inhibitory effects on LPS-induced NO production, and markedly suppressed the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells.

Hyperxylones A and B, two polycyclic polyprenylated acylphloroglucinols with a benzoyl substituted bicyclo[3.2.1]octane core from Hypericum beanii.

Two new polycyclic polyprenylated acylphloroglucinols (PPAPs) possessing a rare benzoyl substituted bicyclo[3.2.1]octane core, hyperxylones A (1) and B (2), along with three new dearomatized isoprenylated acylphloroglucinols (DIAPs), hyperxylones C - E (3-5), were isolated from the roots of Hypericum beanii. The structures of 1-5 were determined by high-resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses, gauge-independent atomic orbital (GIAO) NMR calculations, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were biomimetically semi-synthesized starting from 5 and 4, respectively, enabling the correct stereochemical assignment of 5 and 4. Moreover, compounds 1 and 2 showed anti-nonalcoholic steatohepatitis (NASH) activity by inhibiting lipid deposition in L02 cells; compounds 3 and 5 exhibited nitric oxide (NO) inhibitory activity in lipopolysaccharides (LPS)-induced RAW264.7 cells.

Polycyclic Polyprenylated Acylphloroglucinols Bearing a Lavandulyl-Derived Substituent from Garcinia xanthochymus Fruits.

Many type B polycyclic polyprenylated acylphloroglucinols (PPAPs) bear a lavandulyl-derived substituent, and the configurational assignment of this side chain can be difficult and sometimes leads to erroneous conclusions. In this study, 21 PPAPs, including the new xanthochymusones A-I (1-9), have been isolated from the fruits of Garcinia xanthochymus and structurally characterized. The relative configuration of the C-30 stereocenter was assigned by a combination of chemical transformations, 1H-1H coupling constants, conformational analysis, and NOE experiments. The configurational assignment of compound 7 indicates that the relative configuration at C-30 of PPAPs is not always the same. The absolute configurations of the new compounds were assigned by ECD and X-ray diffraction data, as well as by biosynthetic considerations. Analysis of NMR data enabled the configurational revision of garcicowins C and D. All the isolated PPAPs were tested for antiproliferative activity against three human hepatocellular carcinoma cell lines, including Huh-7, Hep 3B, and HepG2. Compounds 5 and 6, 7-epi-isogarcinol (16), and coccinone C (17) exhibited moderate antiproliferative activity. Compounds 6 and 16 induced apoptosis and inhibited cell migration in Huh-7 cells, probably through downregulating the STAT3 signaling pathway. This study provides effective methods for configurational assignments of type B PPAPs.

Hyperpatone A, a polycyclic polyprenylated acylphloroglucinol with a rare 8/6/5/6/5 pentacyclic skeleton from Hypericum patulum.

Hyperpatone A (1), a highly oxidated polycyclic polyprenylated acylphloroglucinol (PPAP), along with a biosynthesized related PPAP (2) was isolated from Hypericum patulum under the guidance of LC-MS investigation. Architecturally, compound 1 represents the first PPAP with an unprecedented 8/6/5/6/5 pentacyclic skeleton and an intramolecular peroxy bridge, which might be derived from the [3.3.1]-type bicyclic polyprenylated acylphloroglucinol via the critical Baeyer-Villiger oxidation, decarboxylation, and intramolecular cyclization. The structures were established by extensive spectroscopic analysis, ACD software calculation, and quantum chemical computations. A plausible biogenetic pathway of 1 and 2 was also proposed. Importantly, both compounds exhibited moderate cytotoxic activities against the HEL cell line with the IC50 values ranging from 10.2 to 19.2 µM. Moreover, compound 1 showed an inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells at a lower concentration of 5 or 1 µM.

Gallomyrtucommulones G and H, New Phloroglucinol Glycosides, from Bioactive Fractions of Myrtus communis against Staphylococcus Species.

Myrtaceae family is a continuous source of antimicrobial agents. In the search for novel antimicrobial agents against Staphylococcus species, bioactive fractions of Myrtus communis L., growing in the Sardinia island (Italy) have been investigated. Their phytochemical analysis led us to isolate and characterize four alkylphloroglucinol glycosides (1-4), three of them gallomyrtucommulones G-H (1,2), and myrtucommulonoside (4) isolated and characterized for the first time. The structures of the new and known compounds, endopreroxide G3 (5), myricetin-3-O-glycosides (6,7) were determined based on the spectroscopic evidence including 1D-/2D-NMR and HR-MS spectrometry. Enriched fractions as well as pure compounds were tested for their antimicrobial activity by broth micro-dilution assay against Staphylococcus epidermidis and S. aureus. Results reported herein demonstrated that gallomyrtucommulone G (1) showed a selective antimicrobial activity against both S. aureus strains (ATCC 29213 and 43300) until 16 µg/mL while gallomyrtucommulone D (3) showed the best growth inhibition value at 64 µg/mL.

Targeting the biological activity and biosynthesis of hyperforin: a mini-review.

Hyperforin is a representative polycyclic polyprenylated acylphloroglucinols (PPAPs) that exerts a variety of pharmacological activities. The complete biosynthesis pathway of hyperforin has not been elucidated due to its complex structure and unclear genetic background of its source plants. This mini-review focuses on the bioactivity and biosynthesis of hyperforin. These analyses can provide useful insights into the biosynthesis investigations of hyperforin and other PPAPs with complex structures.

Eucarbwenstols A-H, eight novel compounds from Eucalyptus robusta prevents MPC-5 injury via ROS modulation and regulation of mitochondrial membrane potential.

BACKGROUND: The damage of podocytes is a primary hallmark of lupus nephritis (LN). Therefore, finding an effective way to inhibit the podocyte injury is important for improving the survival and development of patients with LN. Eucalyptus robusta exhibits anti-inflammatory properties. However, whether Formyl phloroglucinol meroterpenoids (FPMs), which are specialized metabolites of the genus Eucalyptus, is an anti-inflammatory active ingredient of E. robusta remains to be determined. PURPOSE: This study asimed to identify novel FPMs from E. robusta and investigated their anti-inflammatory effects. METHODS: Various separation methods were used to isolate and identify the compounds in the PE extract of E. robusta. The structures of the isolates were determined using 1D/2D NMR data and electron circular dichroism (ECD) calculations. The level of mitochondrial reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) of the podocyte cell line, MPC-5, were assessed using a multifunctional microplate reader combined with flow cytometry and fluorescence microscopy. RESULTS: Eight novel FPMs (1-8, Eucarbwenstols A-H, Fig. 1) and 15 known FPMs (9-23) were purified from the PE extract of E. robusta. It is noteworthy that compound 1 possesses an unprecedented FPM carbon skeleton. Among these compounds, compounds 1, 2, 4 and 5 showed the most promising potential for protecting MPC-5 cells because pretreatment with pro-inflammatory cytokines TGF-ß, IFN-α and IL-6 decreased ROS production and ameliorated the mitochondrial state. CONCLUSIONS: Our research contributes to the characterization of E. robusta constituents and highlights the anti-inflammatory effects of FPMs.

Discovery of bicyclic polyprenylated acylphloroglucinols from Hypericum himalaicum with glucose transporter 4 translocation activity.

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.

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

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.

Polycyclic polyprenylated acylphloroglucinols from Hypericum beanii and their hepatoprotective activity.

Twenty-seven polycyclic polyprenylated acylphloroglucinols (PPAPs) with diverse skeletons, including seven previously undescribed ones (hyperbeanins A-G), were isolated from the aerial parts of Hypericum beanii. Their structures were established by comprehensive analysis of NMR, HRESIMS, and experimental electronic circular dichroism (ECD) spectra. Hyperbeanin A was a monocyclic polyprenylated acylphloroglucinols (MPAPs) with an unusual spiro-fused cyclopropane ring. Four of the isolated compounds showed obvious hepatoprotective activity against paracetamol-induced HepG2 cell damage at 10 µM. The present results suggested that these compounds would be potential hepatoprotective agents. In addition, the plausible biogenetic pathways of hyperbeanins A-G were proposed, which gave an insight for future biomimetic synthesis of them.

Seco-polyprenylated acylphloroglucinols from Hypericum elodeoides induced cell cycle arrest and apoptosis in MCF-7 cells via oxidative DNA damage.

Four undescribed seco-polyprenylated acylphloroglucinols (seco-PAPs), elodeoidesones A-D (1-4), were characterized from Hypericum elodeoides. Compound 1 represents the 1,6-seco-PAPs with fascinating 5/5 fused ring, while 2-4 possess a 1,2-seco-PAPs skeleton with a five-membered lactone core. Their structures including absolute configurations were established by spectroscopic analyses and quantum chemical computations. A possible biosynthetic pathway of 1-4 from normal PAPs was proposed. All the isolates were investigated for their cytotoxicity against tumor cells. Notably, 1 inhibited the proliferation of MCF-7 cells with the IC50 value of 7.34 µM. Mechanism investigation indicated that 1 induced MCF-7 cells apoptosis by blocking cell cycle at S phase via inducing oxidative DNA damage.

Hypersampones A-C, Three Nor-Polycyclic Polyprenylated Acylphloroglucinols with Lipid-Lowering Activity from Hypericum sampsonii.

Hypersampones A-C (1-3), three unprecedented nor-polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum sampsonii. These compounds represent the first nor-PPAPs with an unexpected tetracyclic 6/5/5/6 ring system. Their structures were assigned through the analysis of detailed spectroscopic data, X-ray crystallography, and electronic circular dichroism calculations. Compound 1 significantly inhibited the accumulation of lipid in an oleic acid-treated HepG2 cell model by suppressing the protein expression of FAS and ACACA at 5 µM.