Phytocannabinoid-like meroterpenoids from twigs and leaves of Rhododendron spinuliferum.

Six pairs of previously undescribed enantiomeric phytocannabinoid-like meroterpenoids, (±)-spinulinoids A‒F, and two naturally occurring compounds, (+)-rhododaurichromanic acid A and (E)-4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)benzoic acid, together with one known congener, (-)-rhododaurichromanic acid A, were obtained from the twigs and leaves of Rhododendron spinuliferum. Their structures were established by their extensive spectral data (NMR and HRESIMS), ECD calculations, and single-crystal X-ray diffraction data. Spinulinoids A and B are unprecedented phytocannabinoid-like meroterpenoids constructed by the resorcinol moiety and a ß-bisabolene unit, whereas spinulinoid C represents a rare adduct of quinone and ß-bisabolene with a tricyclic 6/6/6 ring system.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa.

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a ß-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 µM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

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.

Phloroglucinols with hAChE and α-glucosidase inhibitory activities from the leaves of tropic Rhodomyrtus tomentosa.

Four undescribed phloroglucinol meroterpenoids, rhodotomentodiones A-D, and one undescribed phloroglucinol dimer, rhodotomentodimer A, were obtained and structurally established from tropic Rhodomyrtus tomentosa leaves. Their structures were unambiguously elucidated based on the comprehensive analyses of the NMR and MS spectroscopic data, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction. In particular, rhodotomentodiones A and B represent the first examples of phloroglucinol meroterpenoids featuring a unique γ-pyranoid moiety. More importantly, rhodotomentodimer A exhibited the most potential human acetylcholinesterase (hAChE) and α-glucosidase inhibitory effects with IC50 values of 7.5 µM and 5.6 µM, respectively. The possible interaction sites of the above potential hAChE and α-glucosidase inhibitor were achieved by molecular docking studies. These findings greatly enrich the diversity of natural products from Myrtaceae species, and provide potential candidates for the further development of anti-Alzheimer and antidiabetic diseases.

An unprecedented ergostane with a 6/6/5 tricyclic 13(14 → 8)abeo-8,14-seco skeleton from Talaromyces adpressus.

Talasterone A (1), an unprecedented 6/6/5 tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane steroid, together with two known congeners dankasterone B (2) and (14ß,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (3), were characterized from Talaromyces adpressus. The structure of 1 with absolute configuration was elucidated based on NMR spectroscopic data and ECD calculation. Compound 2 belongs to a class of unconventional 13(14 â†’ 8)abeo-ergostanes, which have been renewed via the 1,2-migration of C-13-C-14 bond to C-8. In addition, compound 1 represents the first example of ergostane with a tricyclic 13(14 â†’ 8)abeo-8,14-seco-ergostane skeleton. The proposed biosynthetic pathway was established with the support of the coisolation of the known congeners from the producing organism. It is especially noteworthy that compound 1 exhibited potent anti-inflammatory activity with an IC50 value of 8.73 ± 0.66 µM, inhibiting the NF-κB pathway and thus reducing the production of proinflammatory cytokines.

Two pairs of undescribed enantiomers isolated from the fungus Penicillium griseofulvum.

Two pairs of undescribed enantiomers including a 2,5-diketopiperazine namely (±)-janthinolide G and a related analogue (±)-janthinolide H, were isolated from the crude extract of the fungus Penicillium griseofulvum together with five known compounds. Both two structures were determined by spectroscopic method and HRESIMS, whereas absolute stereochemistry was elucidated by using theoretical NMR calculation and ECD calculation. Janthinolide G is the first example of 2,5-diketopiperazine enantiomers with a cleavage diketopiperazine ring and comprises a terminal oxime group rarely seen in natural products. Biological screening of selected compounds found that 4 and 7 both exhibited weak α-glucosidase inhibitory effects, and a potential correlation was afforded by docking studies of α-glucosidase protein (PDB: 3TOP) and bioactive molecules. The plausible biosynthetic pathways of two unreported isolates are proposed here.

Thirteen cyathane diterpenoids with acetylcholinesterase inhibitory effects from the fungus Cyathus africanus.

Eight undescribed cyathane diterpenoids, representative specialised metabolites of the genus Cyathus, named cyathins Q-X, along with five known congeners, were isolated from the liquid fermentation of Cyathus africanus. Their structures and absolute configurations were elucidated by integrating NMR spectroscopic analyses, electronic circular dichroism (ECD) calculations, and X-ray diffraction. Reasonable correction to the C-12 configuration of cyathin I was corroborated by the crystal data. The structural identification in this research expanded the number of candidates to allow for more bioactivity-screening options. Among them, (12S)-11α,14α-epoxy-13α,14ß,15-trihydroxycyath-3-ene displayed significant acetylcholinesterase (AChE) inhibitory effect with an IC50 value of 4.60 ± 0.85 µM. Molecular docking studies were also performed to unravel the underlying modes of interactions with the active sites of AChE for active compounds.

Acylphloroglucinol trimers from Callistemon salignus seeds: Isolation, configurational assignment, hAChE inhibitory effects, and molecular docking studies.

Alzheimer's disease (AD) diagnoses are greatly increasing in frequency as the global population ages, highlighting an urgent need for new anti-AD strategies. With the aim to search for human acetylcholinesterase (hAChE) inhibitors from the species of Myrtaceae family, ten acylphloroglucinol trimers (APTs), including eight new APTs, callistemontrimers A-H (1a, 1b, 2a, 2b, 3a, 3b, 4b, and 5b), and two naturally occurring ones (4a and 5a), along with one reported triketone-acylphloroglucinol-monoterpene adduct (6), were obtained and structurally characterized from the hAChE inhibitory acetone extract of Callistemon salignus seeds. The structures and their absolute configurations for new APTs were unequivocally established via the detailed interpretation of extensive spectroscopic data (HRESIMS and NMR), ECD calculations, and single crystal X-ray diffraction, whereas the absolute configurations of known APTs were determined by further chiral separation, and calculated ECD calculations. The results of hAChE inhibitory assay revealed that an enantiomeric mixture of 2a/2b, 2a, and 2b are good hAChE inhibitors with IC50 values of 1.22 ±â€¯0.23, 2.28 ±â€¯0.19, and 4.96 ±â€¯0.39 µM, respectively. Molecular docking was used to uncover the modes of interactions for bioactive compounds with the active site of hAChE. In addition, 2 and 6 displayed moderate neurite outgrowth-promoting effects with differentiation rates of 6.16% and 6.19% at a concentration of 1.0 µM, respectively.

Non-coding RNAs regulating androgen receptor signaling pathways in prostate cancer.

Prostate cancer (PCa) is one of the most common malignancies for men worldwide, and abnormal activation of the androgen receptor (AR) signaling plays an important role in the progression of PCa. However, in the androgen deprivation therapy (ADT), AR signaling inevitably recovered, as a result, exploring novel regulating mechanisms is of great importance. Recently, non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, circular RNAs, could be involved in the progression of PCa, and participate in the regulatory network of AR signaling in a variety of ways. This will help to identify novel molecular mechanisms to promote the development of PCa and find new potential therapeutic targets. In this review, we provide a synopsis of the latest research relating to ncRNAs and associated AR signaling in PCa.

Dongtinganthracenes A-D: Bioxanthracene derivatives from Penicillium sp. DT10 derived from wetland soil obtained from Dongting Lake.

Four undescribed bioxanthracene derivatives, dongtinganthracenes A-D, along with a previously reported analog, ES-242-3, were obtained from the solid culture broth of the fungus Penicillium sp. DT10, which was isolated from wetland soil obtained from Dongting Lake. Their structures and absolute configurations were elucidated based on extensive NMR analyses, mass spectroscopic analyses, and ECD calculations. Dongtinganthracene A represents the first 7',8'-seco-bioxanthracene produced via oxidation, and dongtinganthracenes A-D show a much higher degree of oxidation in aromatic rings compared with normal naturally occurring bioxanthracene derivatives. Dongtinganthracenes B and D and ES-242-3 exhibit cytotoxic activity, while dongtinganthracene A shows inhibitory activity against LPS-induced NO production.

Dongtingnoids A-G: Fusicoccane Diterpenoids from a Penicillium Species.

Five new diterpenoid glycosides, dongtingnoids A-E (1-5), two new diterpenoid aglycones, dongtingnoids F and G (6 and 7), and two known analogues, cotylenins E and J (8 and 9), belonging to the fusicoccane family, were isolated from the fungus Penicillium sp. DT10, which was derived from wetland soil from Dongting Lake. Their structures and absolute configurations were elucidated based on spectroscopic analyses, acid hydrolysis, ECD calculations, and X-ray crystallography. Dongtingnoid C (3) is the first 16-nor-fusicoccane diterpenoid glycoside reported and is proposed to form by oxidative demethylation. Compounds 1, 4, and 5 showed comparable seed-germination-promoting activities to that previously reported for the growth regulator cotylenin E (8).

Withanolides from aerial parts of Nicandra physalodes.

Twenty withanolides, including previously unknown nicanlodes A-M, were isolated from aerial parts of Nicandra physalodes. Their structural elucidations were unambiguously achieved through interpretation of extensive spectroscopic data (NMR and HRMS) and by comparison with literature data. Nicanlodes A and B have an unusual aromatic amine moiety. The isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines.

(±)-Ganoapplanin, a Pair of Polycyclic Meroterpenoid Enantiomers from Ganoderma applanatum.

(±)-Ganoapplanin (1), a pair of novel meroterpenoid enantiomers featuring an unprecedented dioxaspirocyclic skeleton constructed from a 6/6/6/6 tetracyclic system and an unusual tricyclo[4.3.3.03',7']dodecane motif, were isolated from Ganoderma applanatum. Its structure and absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and ECD (electronic circular dichroism calculations). A plausible biogenetic pathway, involving a key Gomberg-Bachmann reaction, was also proposed for (±)-1. Biological studies showed that (±)-1 and its enantiomers exhibited different inhibitory activities on T-type voltage-gated calcium channels.

Cytotoxic Meroterpenoids with Rare Skeletons from Psidium guajava Cultivated in Temperate Zone.

Three new meroterpenoids, guajavadials A-C (1-3), were isolated from Psidium guajava cultivated in temperate zone. Their structures were established by extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. Guajavadial A (1) represents a novel skeleton of the 3,5-diformylbenzyl phloroglucinol-coupled monoterpenoid, while guajavadials B (2) and C (3) are new adducts of the 3,5-diformylbenzyl phloroglucinol and a sesquiterpene with different coupling models. The plausible biosynthetic pathways as well as antimicrobial and cytotoxic activities of these meroterpenoids are also discussed. All these isolates exhibited moderate cytotoxicities against five human cancer cell lines, with 3 being most effective with an IC50 value of 3.54 µM toward SMMC-7721 cell lines.

Cytotoxicity of Triterpenoid Alkaloids from Buxus microphylla against Human Tumor Cell Lines.

Three new triterpenoid alkaloids, namely buxmicrophyllines P-R (1-3), were isolated from the twigs and leaves of Buxus microphylla. Their structures were elucidated on the basis of NMR and MS spectroscopic analyses. Structurally, compounds 1-3 belong to the 9,10-cycloartane type alkaloids. In addition, compound 3 exhibited moderate cytotoxic activities in vitro against HL-60, SMMC-7221, A-549, MCF-7, and SW480 cell lines (with IC50 values ranging from 4.51 to 15.58 µM).

Pepluane and Paraliane Diterpenoids from Euphorbia peplus with Potential Anti-inflammatory Activity.

Twelve new diterpenoids based on two rare skeletal types, namely, paralianones A-D (1-4) and pepluanols A-H (5-12), along with five known compounds, were isolated from an acetone extract of Euphorbia peplus. Their structures were proposed based on 1D and 2D NMR spectroscopic data analysis. These diterpenoids were evaluated for potential anti-inflammatory activity in a lipopolysaccharide-stimulated mouse macrophage cellular model. Compounds 3, 4, 11, 13, and 16 displayed moderate inhibitory effects on NO inhibition, with IC50 values ranging from 29.9 to 38.3 µM.

Characterization of New Ent-kaurane Diterpenoids of Yunnan Arabica Coffee Beans.

Five new ent-kaurane diterpenoids, named mascaroside III-V (1-3), and 20-nor-cofaryloside I-II (4-5), together with seven known diterpenoids, were isolated from methanol extracts of the green coffee beans of Yunnan Arabica Coffee. Their chemical structures were elucidated by extensive spectroscopic analyses. Meanwhile, cytotoxicity assay against HL-60, A-549, SMMC-7721, MCF-7 and SW480 cell lines showed that they have not evident inhibition of cytotoxicity.

Steroidal saponins from stems and leaves of Paris polyphylla var. yunnanensis.

Phytochemical investigation of the stems and leaves of Paris polyphylla var. yunnanensis led to isolation of 12 steroidal saponins, chonglouosides SL-9-SL-20, which had not been described previously, along with 13 known compounds. Their structures were established on the basis of extensive spectroscopic analysis and chemical methods. Four of the twelve steroidal saponins possessed three steroidal aglycones which have not been reported in nature. Steroidal saponins were also evaluated for their cytotoxicities against two human cancer cell lines (HepG2 and HEK293) and anti-HCV effects. One known steroidal saponin was the most cytotoxic compound overall with IC50 values of 2.9 ± 0.5 µM and 5.0 ± 0.6 µM against HepG2 and HEK293 cell lines, respectively, while none showed anti-HCV activity at a concentration of 20 µM.

Biflavone Ginkgetin, a Novel Wnt Inhibitor, Suppresses the Growth of Medulloblastoma.

Medulloblastoma (MB) is a form of malignant brain tumor that predominantly arises in infants and children, of which approximately 25 % is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1. Therefore, Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer. In our present study, we undertook a screening for antagonists of Wnt signaling from 600 natural compounds, and identified Ginkgetin, a biflavone isolated from Cephalotaxus fortunei var. alpina. Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 µM and structure-activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group. Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells. Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells. Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes, including Axin2, cyclinD1 and survivin in MB cells. The phosphorylation level of ß-catenin also decreased in a time- and concentration-dependent manner. Collectively, our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling, and as such warrants further exploration as a promising anti-medulloblastoma candidate.