Three New Ionone Glycosides from Rhododendron capitatum Maxim.

Six ionone glycosides (1-3 and 5-7), including three new ones, named capitsesqsides A-C (1-3), together with an eudesmane sesquiterpenoid glycoside (4) and three known triterpenoid saponins (8-10) were isolated from Rhododendron capitatum. The structures of these compounds were determined by extensive spectroscopic techniques (MS, UV, 1D-NMR, and 2D-NMR) and comparison with data reported in the literature. The absolute configurations were determined by comparison of the experimental and theoretically calculated ECD curves and LC-MS analyses after acid hydrolysis and derivatization. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. Molecular docking demonstrated that 2 has a favorable affinity for NLRP3 and iNOS.

Discovery of Unusual Sesterterpenoids from Colquhounia coccinea var. mollis and Their Metabolic Implications.

Three unusual sesterterpenoids featuring unprecedented rearranged colquhounane (C25) and tetranorcolquhounane (C21) frameworks, colquhounoids E (1) and F (3) and norcolquhounoid F (2), were isolated from a Lamiaceae medicinal plant Colquhounia coccinea var. mollis. Their structures were elucidated by spectroscopic analysis and quantum chemical calculations. A biomimetic inspired regioselective cyclopropane cleavage was achieved under acidic conditions. The immunosuppressive activities of these new sesterterpenoids were also evaluated.

A new anti-neuroinflammation labdane diterpenoid from Salvia tricuspis.

One new labdane diterpenoid, tricuspion A (1), as well as five known triterpenoids (2-6) were isolated from Salvia tricuspis Franch (family Labiatae). The structure of tricuspion A was identified by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 1-6 were evaluated for their inhibitory effects on the NO production in LPS-stimulated BV-2 microglia cells, and 1 exhibited potent inhibitory activity with IC50 value of 14.92 ± 0.51 µM. Compound 1 might exert anti-neuroinflammatory activity through inhibiting the excessive production of NO and down-regulating the protein expression of iNOS and COX-2. As such, labdane diterpenoid (tricuspion A) could provide promising anti-neuroinflammatory lead compound for further structural modification.

Diversified cassane family diterpenoids from the leaves of Caesalpinia minax exerting anti-neuroinflammatory activity through suppressing MAPK and NF-κB pathways in BV-2 microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia minax Hance, whose seeds are known as "Ku-shi-lian" in China, have been used in Chinese folk medicine for treatment of rheumatism, dysentery, and skin itching. However, the anti-neuroinflammatory constituents of its leaves and their mechanism are rarely reported. AIM OF THE STUDY: To search for new anti-neuro-inflammatory compounds from the leaves of C. minax and elucidate their mechanism on anti-neuroinflammatory effect. MATERIALS AND METHODS: The main metabolites of the ethyl acetate fraction from C. minax were analyzed and purified via HPLC and various column chromatography techniques. Their structures were elucidated on the basis of 1D and 2D NMR, HR-ESI-MS, and single crystal X-ray diffraction analysis. Anti-neuroinflammatory activity was evaluated in BV-2 microglia cells induced by LPS. The expression levels of molecules in NF-κB and MAPK signaling pathways were analyzed through western blotting. Meanwhile, the time- and dose-dependent expression of associated proteins such as iNOS and COX-2 were detected by western blotting. Furthermore, Compounds 1 and 3 were performed on the NF-κB p65 active site using molecular docking simulation to elucidate the molecular level inhibition mechanism. RESULTS: 20 cassane diterpenoids, including two novel ones (caeminaxins A and B) were isolated from the leaves of C. minax Hance. Caeminaxins A and B possessed a rare unsaturated carbonyl moiety in their structures. Most of the metabolites exhibited potent inhibition effects with IC50 values ranging from 10.86 ± 0.82 to 32.55 ± 0.47 µM. Among them, caeminaxin A inhibited seriously the expression of iNOS and COX-2 proteins and restrained the phosphorylation of MAPK and the activation of NF-κB signaling pathways in BV-2 cells. The anti-neuro-inflammatory mechanism of caeminaxin A has been studied systematically for the first time. Furthermore, biosynthesis pathways for compounds 1-20 were discussed. CONCLUSIONS: The new cassane diterpenoid, caeminaxin A, alleviated the expression of iNOS and COX-2 protein and down-regulated of intracellular MAPK and NF-κB signaling pathways. The results implied that cassane diterpenoids had potential to be developed into therapeutic agents for neurodegenerative disorders such as Alzheimer's disease.

Phytoecdysteroids from Dianthus superbus L.: Structures and anti-neuroinflammatory evaluation.

Six undescribed C27-phytoecdysteroid derivatives, named superecdysones A-F, and ten known analogs were extracted from the whole plant of Dianthus superbus L. Their structures were identified by extensive spectroscopy, mass spectrometric methods, chemical transformations, chiral HPLC analysis, and the single-crystal X-ray diffraction analysis. Superecdysones A and B possess a tetrahydrofuran ring in the side chain and superecdysones C-E are rare phytoecdysones containing a (R)-lactic acid moiety, whereas superecdysone F is an uncommon B-ring-modified ecdysone. Notably, based on the variable temperature (from 333 K to 253 K) NMR experiments of superecdysone C, the missing carbon signals were visible at 253 K and assigned. The neuroinflammatory bioassay of all compounds were evaluated, and 22-acetyl-2-deoxyecdysone, 2-deoxy-20-hydroxyecdysone, 20-hydroxyecdysone, ecdysterone-22-O-benzoate, 20-hydroxyecdysone-20,22-O-R-ethylidene, and acetonide derivative 20-hydroxyecdysterone-20, 22-acetonide significantly suppressed the LPS-induced nitric oxide generation in microglia cells (BV-2), with IC50 values ranging from 6.9 to 23.0 µM. Structure-activity relationships were also discussed. Molecular docking simulations of the active compounds confirmed the possible mechanism of action against neuroinflammations. Furthermore, none compounds showed cytotoxicity against HepG2 and MCF-7. It is the first report about the occurrence and anti-neuroinflammatory activity of the phytoecdysteroids in the genus Dianthus. Our findings demonstrated that ecdysteroids may be used as potential anti-inflammatory drugs.

Discovery of diversified cassane diterpenoids as potent antibacterial agents from Caesaplinia pulcherrima and their mechanisms.

BACKGROUND: Natural products play a significant role in the development of novel bactericide candidates. Caesalpinia pulcherrima, a traditional medicine, had anti-inflammatory, antimicrobial, and antifeedant activities, therefore the previous bioassay results of C. pulcherrima implied that its main active ingredients may have potential to be used as botanical bactericides. RESULTS: Bio-guided isolation of C. pulcherrima was conducted to obtain 11 novel cassane diterpenoids (capulchemins A-K) and 10 known sesquiterpenes. Their structures were established by extensive spectroscopic methods and single-crystal X-ray diffraction analyses. Capulchemins A-F possess a rare aromatic C ring, while capulchemin K with a 15,16-degradative carbon skeleton represents a rare group of cassane diterpenes. Capulchemin A exhibited remarkable antibacterial activity against four phytopathogenic bacteria, particularly against Pseudomonas syringae pv. actinidae and Bacillus cereus, with minimal inhibitory concentration values of 3.13 µM. Meanwhile, capulchemin A showed significant control effect on kiwifruit canker in vivo. Further investigation of its mechanism of antibacterial activity revealed that compound 1 was closely related to destroy cell membrane to cause cell death. Additionally, some of those cassane diterpenoids showed potential antifeedant against Mythimna separate walker and Plutella xylostella. Consequently, capulchemin A could have the potential to be used as a template for the development for new eco-friendly NP-based bactericides. CONCLUSION: These data contribute to a better understanding of the antibacterial activity of cassane diterpenes. Cassane diterpenes have been discovered to be leading to broad application prospects in the development as novel botanical bactericides. © 2023 Society of Chemical Industry.

Labdane diterpenoids from the heartwood of Leucosceptrum canum that impact on root growth and seed germination of Arabidopsis thaliana.

Eleven undescribed diterpenoids possessing labdane, 3,18-cyclo-labdane, 19 (4 â†’ 3)-labdane and 12-nor-labdane skeletons, named leucolactones A-K, were isolated from the heartwood of a large woody Lamiaceae plant, Leucosceptrum canum. Their structures were determined by NMR, MS, and in the case of leucolactones A by single crystal X-ray diffraction analysis. Plausible biosynthetic pathway of leucolactones were proposed. Leucolactones showed significant inhibitory effects against seed germination and root elongation of Arabidopsis thaliana in the Petri dish bioassay. Among them, the diastereomeric leucolactones G and H were the most potent, with EC50 values for root elongation of 6.53 ± 1.35 and 9.75 ± 1.25 µM, respectively. The preliminary structure-activity relationship of leucolactones was discussed. The increase of auxin reporter activity in A. thaliana DR5::GUS roots by leucolactone H was observed, indicating that leucolactones altered auxin accumulation and distribution. These findings suggested that leucolactones might be involved in regulation of plant growth and development through altering auxin accumulation and distribution, presumably contributing to the heartwood formation in L. canum.

Cassane diterpenoids from the aerial parts of Caesalpinia pulcherrima and their antibacterial and anti-glioblastoma activity.

Sixteen cassane diterpenoids (CAs), including four undescribed lactam-type, four unreported lactone-type, along with eight known ones, were isolated from the aerial parts of Caesalpinia pulcherrima (L.) Sw. Their structures were characterized by comprehensive spectroscopic analyses (including NMR and HRESIMS). The absolute configuration of pulcherritam A was finally established by single-crystal X-ray diffraction with Cu Kα radiation. Notably, pulcherritam s A-D were elucidated as a group of rare CAs bearing an α, ß-unsaturated γ-lactam ring rather than a typical lactone moiety. Almost all compounds were examined for their antibacterial. The results reveal that pulcherritam H exhibited significant antibacterial activities against Bacillus cereus, Staphylococcus aureus, as well as Pseudomonas syringae pv. actinidae (Psa) with the MIC from 6.25 to 12.5 µM, while pulcherritams A and C displayed potent antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA). Then, all isolates were evaluated for their anti-glioblastoma activities. Pulcherritam A and Pulcherrimin G illustrated moderate inhibitory activity against glioblastoma multiforme (GBM) U87MG cell, and the other compounds did not show obvious inhibitory activity against GBM U87MG cell. Furthermore, the preliminary structure-activity relationship and their biosynthetic pathway were also discussed.

Cassane diterpenoids from Caesalpinia pulcherrima and their anti-inflammatory and α-glycosidase inhibitory activities.

Three undescribed cassane-type diterpenoids (CAs), caesalpulcherrins K-M (1-3), together with three known ones (4-6) were isolated from the aerial parts of Caesalpinia pulcherrima (L.) Sw (Fabaceae). Their structures were elucidated via analysis of NMR (1 D and 2 D) and HRESIMS data. The character for caesalpulcherrin K possessing the olefin bond at C-11 and C-12 in its cassane skeleton was observed, which belonged to a small group among more than 450 CAs. That is, only fifteen derivatives have been reported up to now, to our knowledge. Biological evaluation revealed that compounds 1-6 exhibited moderate anti-inflammatory activity, with an IC50 value from 6.04 ± 0.34 to 8.92 ± 0.65 µM. Furthermore, compounds 5 and 6 exhibited significant α-glucosidase inhibitory activity at 10 µM.

Immunosuppresive Sesterterpenoids and Norsesterterpenoids from Colquhounia coccinea var. mollis.

A pair of new C-14 epimeric sesterterpenoids, colquhounoid D (1) and 14-epi-colquhounoid D (2), and five degradation products featuring new C20 and C21 frameworks, norcolquhounoids A-E (3-7), were isolated from Colquhounia coccinea var. mollis. Their structures were elucidated by comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Degradation of the C25 skeleton to the C21 skeleton was also achieved using aqueous NaIO4 and RuCl3. Compounds 1 and 2 showed significant immunosuppressive activity on the cytokine IFN-γ secretion of mouse splenocytes induced by anti-CD3/CD4 monoclonal antibodies, with IC50 of 8.38 and 5.79 µM, respectively, and compounds 5 and 6 were moderately active.

Cassane Diterpenoids from the Aerial Parts of Caesalpinia pulcherrima and Their Antifeedant and Insecticidal Activities against Mythimna separate and Plutella xylostella.

Ten new cassane diterpenoids, caesalpulcherrins A-J (1-10), together with 11 known analogues (11-21) were isolated from the aerial parts of Caesalpinia pulcherrima. Their structures and relative stereochemistry were elucidated by spectrometric and spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and single-crystal X-ray diffraction analysis. Compounds 1-4 represent the first examples of 2,5-dimethoxyfuranocassane diterpenoids. Results of the antifeedant activity indicated that isovouacapenol C (12) and pulcherrin N (14) exhibited remarkable antifeedant activity against Mythimna separate with EC50 values of 3.43 and 4.20 µg/cm2, respectively. Meanwhile, pulcherrimin C (13) and 12-demethyl neocaesalpin F (18) exerted significant antifeedant activity against Plutella xylostella with an EC50 data of 4.00 and 3.05 µg/cm2, respectively. Some of the compounds showed obvious toxic activity against the plant-feeding generalist insect herbivores, M. separate and P. xylostella, at 0.8 mg/mL (800 ppm). Furthermore, the structure-activity relationships of antifeedant and insecticidal activities are also discussed in the article.

Peltate glandular trichomes of Colquhounia vestita harbor diterpenoid acids that contribute to plant adaptation to UV radiation and cold stresses.

Plant glandular trichomes (GTs) are adaptive epidermal structures that synthesize and accumulate diverse specialized metabolites well-known as defense chemicals against biotic attacks, but their roles against abiotic challenges including UV radiation and cold climates remain largely unexplored. Colquhounia vestita Wall is a Chinese-Himalayan Lamiaceae plant with dense peltate and capitate GTs on its leaf and stem surfaces under a scanning electron microscope. Three diterpenoid acids, including a clerodane 5-epi-hardwickiic acid and two labdanes polyalthic acid and E-communic acid, were identified from the peltate GTs of C. vestita through laser microdissection coupled with UPLC-MS/MS. Under UV radiation and cold stresses, the major GT component polyalthic acid increased the biomass of Arabidopsis thaliana seedlings and decreased their malondialdehyde content. Furthermore, polyalthic acid promoted photosynthetic efficiency and the expression of genes encoding peroxidative enzymes under UV radiation, and stimulated Ca2+ elevation and the expression of calmodulin binding transcription activator gene CAMTA3 and two downstream cold-responsive genes CBF3 and RD29A under cold stress. Therefore, polyalthic acid in GTs is likely to endow the plant with enhanced tolerance to UV radiation and cold stresses, which extends the current understanding of the function of GT compounds in plant adaptation to abiotic environments.

An overview of grayanane diterpenoids and their biological activities from the Ericaceae family in the last seven years.

Grayanane diterpenoids, possessing a unique 5/7/6/5 tetracyclic system, exist exclusively in plants of the Ericaceae family. Owing to their various skeletons, complex structures, and diverse bioactivities, grayanoids have been the topic of research in many phytochemical and pharmacological laboratories, offering opportunities for the development of new drugs with analgesic, anti-inflammatory, and protein tyrosine phosphatase 1B (PTP1B) properties. Recently, a number of new grayanane diterpenoids with unprecedented carbon skeletons have been obtained from plants of the Ericaceae family, and they exhibit diverse biological properties, such as agalgesic, antinociceptive, anticancer, antiviral, antifeedant, insecticidal, toxicity, and PTP1B. In this review, 162 new grayanoids with 14 carbon skeletons from the Ericaceae family over the past seven years (2012-October 2018) are discussed, including their occurrence and distribution, skeleton types, structural features, biological activities, and structure-activity relationships (SARs). Also, strategies for the structural elucidation are summarized to provide useful information for medicinal chemists in developing potent anticancer, antiviral, analgesic, anti-inflammatory, and novel PTP1B agents.

Polycyclic polyprenylated acylphloroglucinol and phenolic metabolites from the aerial parts of Hypericum elatoides and their neuroprotective and anti-neuroinflammatory activities.

A phytochemical study on the aerial parts of Hypericum elatoides led to the isolation of a previously undescribed polycyclic polyprenylated acylphloroglucinol derivative, hyperelatone A, seven previously undescribed phenolic metabolites, hyperelatones B-H, along with ten known analogues. The structures of hyperelatones A-H were elucidated by 1D and 2D NMR spectroscopy, HRESIMS experiment, single-crystal X-ray diffraction and comparison of experimental and calculated ECD spectra, as well as chemical derivatization. All compounds were evaluated for their neuroprotective activity against hydrogen peroxide (H2O2)-induced cell injury in rat pheochromocytoma PC-12 cells and inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells. Hyperelatones B-D and H, cinchonain Ib, and tenuiside A showed noticeable neuroprotection at concentrations of 1.0-100.0 µM. Hyperelatones D, G, and H, (-)-epicatechin, tenuiside A, and (Z)-3-hexenyl-ß-D-glucopyranoside exhibited significant anti-neuroinflammatory activity with IC50 values ranging from 0.75 ±â€¯0.02 to 5.83 ±â€¯0.23 µM.

Hyperelatosides A-E, biphenyl ether glycosides from Hypericum elatoides, with neurotrophic activity.

Five new biphenyl ether glycosides, hyperelatosides A-E (1-5), one new benzoate glycoside, hyperelatoside F (6), along with nine known phenolic compounds (7-15), were isolated from the aerial parts of Hypericum elatoides. Their structures were elucidated by 1D and 2D NMR spectroscopy and HRESIMS, as well as chemical derivatization. This is the first report of the identification of biphenyl ether glycosides as plant metabolites and their possible biosynthetic pathway is proposed. Except for 3, the new phenolic metabolites exhibited significant neurotrophic activities to enhance nerve growth factor-induced neurite outgrowth in PC12 cells. In addition, the anti-neuroinflammatory and antioxidant activities of compounds 1-15 were preliminarily evaluated in vitro.

Structural Diversity and Biological Activity of the Genus Pieris Terpenoids.

Secondary metabolites, particularly the grayanane diterpenoids produced by the members of genus Pieris, have been investigated in past decades for their remarkable antifeedant and insecticidal activities and toxicity. Grayanoids exhibit diverse biological properties such as antifeedant, insecticidal, cAMP regulatory, and sodium-channel-modulating activities. Structural complexity and diverse bioactivity of grayanoids have made them attractive targets for chemical, biological, and synthetic purposes. The current review synthesized findings published from 1966 to 2017, which include 135 reports that describe 130 terpenoids, including 103 grayanoids. The distribution, structure, skeleton, as well as the antifeedant and insecticidal activity of terpenoids, particularly the grayanane diterpenoids, are discussed in detail in this review. In cases where sufficient information is available, the structure-activity relationships of their antifeedant activity are also presented. We hope that this contribution will prompt more scientists to pay attention to these diterpenoids, which may be potentially applied in the agricultural field.

New Antifeedant Grayanane Diterpenoids from the Flowers of Pieris formosa.

Three new grayanane diterpenoids, pierisoids C‒E (1-3), as well as 10 known ones (4-13), were evaluated from the flowers of Pieris formosa, which is used as an insecticide in rural areas of China. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses. Significant antifeedant activity of 1, 3 and 10 against the beet armyworm (Spodoptera exigua) was found, indicating that these diterpenoids might also be involved in the plant defense against insect herbivores.

Isobutylhydroxyamides from Zanthoxylum bungeanum and Their Suppression of NO Production.

Four new unsaturated aliphatic acid amides, named zanthoamides A-D (1-4), and eight known ones-tetrahydrobungeanool (5), ZP-amide A (6), ZP-amide B (7), ZP-amide C (8), ZP-amide D (9), ZP-amide E (10), bugeanumamide A (11), and (2E,7E,9E)-N-(2-hydroxy-2-methylpropyl)-6,11-dioxo-2,7,9-dodecatrienamide (12)-were isolated from the pericarps of Zanthoxylum bungeanum. The structures of these compounds were elucidated by extensive use of spectroscopic methods, including HRESIMS, 1D and 2D NMR analyses and comparison with previously reported data. Compound 4 contained a rare C6 fatty acid unit with an acetal group. Results revealed that compounds 1, 5, 6, and 12 showed inhibitory effects on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages, with IC50values of 48.7 ± 0.32, 27.1 ± 1.15, 49.8 ± 0.38, and 39.4 ± 0.63 µM, respectively, while the other compounds were inactive (IC50 > 60 µM). They could contribute to the anti-inflammatory effects of Z. bungeanum by suppression of NO production.

A Geranylfarnesyl Diphosphate Synthase Provides the Precursor for Sesterterpenoid (C25) Formation in the Glandular Trichomes of the Mint Species Leucosceptrum canum.

Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing the C25 prenyl diphosphate precursor to all sesterterpenoids, from the glandular trichomes of the woody plant Leucosceptrum canum. GFDPS catalyzed the formation of GFDP after expression in Escherichia coli. Overexpressing GFDPS in Arabidopsis thaliana also gave an extract catalyzing GFDP formation. GFDPS was strongly expressed in glandular trichomes, and its transcript profile was completely in accordance with the sesterterpenoid accumulation pattern. GFDPS is localized to the plastids, and inhibitor studies indicated its use of isoprenyl diphosphate substrates supplied by the 2-C-methyl-D-erythritol 4-phosphate pathway. Application of a jasmonate defense hormone induced GFDPS transcript and sesterterpenoid accumulation, while reducing feeding and growth of the generalist insect Spodoptera exigua, suggesting that these C25 terpenoids play a defensive role. Phylogenetic analysis suggested that GFDPS probably evolved from plant geranylgeranyl diphosphate synthase under the influence of positive selection. The isolation of GFDPS provides a model for investigating sesterterpenoid formation in other species and a tool for manipulating the formation of this group in plants and other organisms.

Unraveling the metabolic pathway in Leucosceptrum canum by isolation of new defensive leucosceptroid degradation products and biomimetic model synthesis.

Seven new leucosceptroid degradation products possessing a C20, C21, or C25 framework, norleucosceptroids D-H (1-5), leucosceptroids P (6), and Q (7), have been isolated from Leucosceptrum canum. Their structures were determined by comprehensive NMR, MS, and single-crystal X-ray diffraction analyses. Discovery of these key intermediates, together with the biomimetic oxidation of a model system, supports the hypothesis that two biosynthetic pathways are operative. Antifeedant activity was observed for compounds 1-3.