Triterpenoids from the Leaves of Diospyros digyna and Their PTP1B Inhibitory Activity.

Six new 2α-hydroxy ursane triterpenoids, 3α-cis-p-coumaroyloxy-2α,19α-dihydroxy-12-ursen-28-oic acid (1), 3α-trans-p-coumaroyloxy-2α,19α-dihydroxy-12-ursen-28-oic acid (2), 3α-trans-p-coumaroyloxy-2α-hydroxy-12-ursen-28-oic acid (3), 3ß-trans-p-coumaroyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (4), 3ß-trans-feruloyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (5), and 3α-trans-feruloyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (6), along with eleven known triterpenoids (7-17), were isolated from the leaves of Diospyros digyna. Their chemical structures were elucidated by comprehensive analysis of UV, IR, HRESIMS, and NMR spectra. All the isolated compounds were evaluated for their PTP1B inhibitory activity. 3ß-O-trans-feruloyl-2α-hydroxy-urs-12-en-28-oic acid (13) showed the best inhibition activity with an IC50 value of 10.32 ± 1.21 µM. The molecular docking study found that the binding affinity of compound 13 for PTP1B was comparable to that of oleanolic acid (positive control).

Triterpenoids and triterpenoid saponins from Vitex negundo and their anti-inflammatory activities.

Seven undescribed polyoxygenated ursane-type triterpenoids (vitnegundins A-G), three undescribed triterpenoid saponins (vitnegundins H-J), and 17 known ones were isolated from an EtOH extract of the aerial parts of Vitex negundo L. The structures of the undescribed compounds were established by extensive spectroscopic analysis. The absolute configurations of vitnegundins A, B, and E were determined by single-crystal X-ray diffraction data. Vitnegundins B-D are pentacyclic triterpenoids possessing rare cis-fused C/D rings and vitnegundins C-H represent undescribed ursane-type triterpenoids with 12,19-epoxy moiety. In the biological activity assay, vitnegundin A, vitnegundin E, and swinhoeic acid displayed inhibitory effects against LPS-induced NO release in BV-2 microglial cells, with IC50 values of 11.8, 44.2, and 19.6 µM, respectively.

Pentacyclic triterpenes from the leaves of Camellia hakodae Ninh.

Nine pentacyclic triterpene derivatives including new 3-O-cis-p-coumaroyl trichadenic acid B (1) and two new ursane-type triterpene derivatives, 11α,12-[1-(methyl)-2-(4-hydroxy-3-methoxyphenyl)ethane-1,2-dioxy]-urs-12-ene-3ß-ol (2) and 11α,12-[2-(methyl)-1-(4-hydroxy-3-methoxyphenyl)ethane-1,2-dioxy]-urs-12-ene-3ß-ol (3) were isolated from the leaves of Camellia hakodae Ninh., along with six known compounds (4-9). This is the first report on pentacyclic triterpenoids from this species. New compounds 1-3 and compound 7 were tested for cytotoxic activity against four human cancer cell lines (KB; Hep-G2; Lu; MCF-7) using the MTT assay to show moderate activity.

Ilexchinene, a new seco-ursane triterpenoid from the leaves of Ilex chinensis with therapeutic effect on neuroinflammation by attenuating the MAPK/NF-κB signaling pathway.

BACKGROUND: Neuroinflammation is a vital factor participating in the whole pathogenetic process of diverse neurodegenerative disorders, but accessible clinical drugs are still insufficient due to their inefficacy and side effects. Triterpenoids are reported to possess potential anti-neuroinflammatory activities, and the leaves of Ilex chinensis are a commonly used herbal medicine containing many ursane-type and oleanane-type triterpenoids. However, the novel triterpenoids from I. chinensis and their underlying mechanisms are still elusive. PURPOSE: To isolate novel seco-ursane triterpenoids with anti-neuroinflammatory effects from the leaves of I. chinensis and reveal their underlying mechanisms. STUDY DESIGN AND METHODS: The novel compound was purified by column chromatography and identified by comprehensive spectroscopic experiments. The LPS-induced BV-2 cell model and LPS-induced acute murine brain inflammation model were used to assess the anti-neuroinflammatory effect of the structure and further understand its underlying mechanisms by cell viability, ELISA, Western blot analysis, qRT‒PCR analysis, behavior analysis, H&E staining, and immunofluorescence staining experiments. RESULTS: Ilexchinene is a novel ursane-type triterpenoid with a rare 18,19-seco-ring skeleton that was first isolated and identified from I. chinensis. Ilexchinene evidently reduced the overexpression of inflammatory substances in vitro. A mechanistic study suggested that ilexchinene could decrease NF-κB activation to prevent the formation of the NLRP3 inflammasome in the early neuroinflammatory response; in addition, it could prevent the phosphorylation of ERK and JNK. In vivo, ilexchinene remarkably improved LPS-induced mouse behavioral deficits and diminished the number of overactivated microglial cells. Furthermore, ilexchinene evidently diminished the overexpression of inflammatory substances in mouse brains. A mechanistic study confirmed that ilexchinene markedly suppressed the MAPK/NF-κB pathway to relieve the neuroinflammatory response. CONCLUSION: We identified a novel 18,19-seco-ursane triterpenoid from the leaves of I. chinensis and revealed its underlying mechanism of neuroinflammation for the first time. These findings suggest that ilexchinene might possess promising therapeutic effects in neuroinflammation.

Saponins of Selected Triterpenoids as Potential Therapeutic Agents: A Review.

Saponins represent important natural derivatives of plant triterpenoids that are secondary plant metabolites. Saponins, also named glycoconjugates, are available both as natural and synthetic products. This review is focused on saponins of the oleanane, ursane, and lupane types of triterpenoids that include several plant triterpenoids displaying various important pharmacological effects. Additional convenient structural modifications of naturally-occurring plant products often result in enhancing the pharmacological effects of the parent natural structures. This is an important objective for all semisynthetic modifications of the reviewed plant products, and it is included in this review paper as well. The period covered by this review (2019-2022) is relatively short, mainly due to the existence of previously published review papers in recent years.

Three new triterpenoid glycosides from Aronia melanocarpa (Michx.) Elliott.

Three new triterpenoid glycosides, 2α,3α,23,24-tetrahydroxyurs-12,19- dien-oic acid 28-O-ß- D -glucopyranoside (1), 2α,3ß,23,24-tetrahydroxyurs-12, 19(29) -dien-28-oic acid 28-O-ß- D -glucopyranoside (2), and 2α,3ß,23,24-tetrahydroxyurs-12, 18-dien-28-oic acid 28-O-ß- D -glucopyranoside (3) were isolated from Aronia melanocarpa (Michx.) Elliott. Their structures were elucidated by extensive spectroscopic methods. All the isolated compounds displayed moderate inhibitory activity against nitric oxide production in macrophages.

Methyl 2-naphthoates with anti-inflammatory activity from Morinda officinalis.

Chemical fractionation of the EtOH extract of the roots of a traditional Chinese herb, Morinda officinalis, afforded an array of methyl 2-naphthoate derivatives (1-9) including four pairs of enantiomers (1-4), two pimarane diterpenes and two ursane triterpenoids. Among them, eight compounds (1a/1b-3a/3b, 11 and 13) were reported in the current work for the first time. The structures of the new compounds, including their absolute configurations, were defined by spectroscopic analyses in combination with quantum chemical electronic circular dichroism (ECD) and gauge-independent atomic orbital (GIAO) NMR calculations. All the isolates were evaluated for their inhibitory effect on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine RAW264.7 macrophage cells, and the enantiomers 1a and 3b exhibited moderate activity with IC50 values of 41.9 and 26.2 µM. Meanwhile, compound 3b also dose-dependently inhibited the secretion of two pro-inflammatory cytokines TNF-α and IL-6 in the same cell model.

Two new ursane triterpenoids from Agastache rugosa (Fisch. et.Mey.) O. Kuntze / 药学学报

Two new ursane triterpenoids along with twelve known compounds were isolated from 80% ethanol extract of Agastache rugosa (Fisch. et. Mey.) O. Kuntze by using silica gel column, MCI column, ODS column and HPLC. The structures of the new compounds were identified as 2α,3α-dihydroxy-24-nor-urs-4(23),12(13)-dien-28-oic acid (1) and 2α,3α-dihydroxy-24-nor-urs-4(23),12(13),20(30) -trien-28-oic acid (2) by HR-ESI-MS, NMR and ECD spectral data, named agasursacid A and agasursacid B. In addition, compounds 3, 4, 6, 8 showed anti-coxsackievirus B3 (CVB3) activities with a IC50 as 4.77, 1.59, 11.11 and 25.87 μmol·L-1, resepectively.

Ursane and 24-Noroleanane-Type Triterpenoids with Anti-HIV Activity from the Twigs and Leaves of Antirhea chinensis.

Investigations on the twigs and leaves of Antirhea chinensis have led to the discovery of two undescribed pentacyclic triterpenoids (1 and 2) and nine known analogs. Compounds 1 and 2, each assigned as the ursane and 24-noroleanane-type triterpenoids, featuring similar oxidation pattern of 3ß,6ß,19α-trihydroxy-28-carboxyl. Their structures were elucidated via comprehensive analyses of spectroscopic data. Compound 1 displayed potent anti-HIV activity (EC50 =1.24 µM) and high selectivity index (SI >32.3).

Abietane-Type Diterpenoids From Nepeta bracteata Benth. and Their Anti-Inflammatory Activity.

Terpenes possess a wide range of structural features and pharmaceutical activities and are promising for drug candidates. With the aim to find bioactive terpene molecules, eight new compounds were isolated from the medicinal plant Nepeta bracteata Benth., including seven new abietane-type diterpenoids (1-7), along with a new ursane-type triterpenoid (8). The structures of compounds 1-8 were elucidated through the detailed spectroscopic analyses of their 1D and 2D NMR and MS data, and the absolute configurations of compounds 1-7 were determined by comparing their experimental and calculated ECD spectra. Compound 1 was a novel degraded carbon diterpene with the disappearing of methyl signal at C-19, while compound 7 possessed a new norabietane-type diterpenoid carbon skeleton with the presence of five-membered lactone arising from ring rearrangement. The anti-inflammatory of all obtained isolates were evaluated on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the results of anti-inflammatory activity screening showed that compared with the LPS model group, all compounds were significantly down-regulation the TNF-α inflammatory factor at the specific concentration, except for compound 6.

Anti-COVID-19 and antidiabetic activities of new oleanane and ursane-type triterpenoids from Salvia grossheimii: an in-silico approach.

Salvia grossheimii is a perennial herb with antidiabetic and cytotoxic constituents. In continuation of our study on S. grosshiemii to identify the bioactive phytochemicals, we have reported the characterization of seven undescribed triterpenoids. The aerial parts of the plant were extracted in dichloromethane and its constituents were isolated using chromatography techniques. The structures of compounds were identified using 1D, 2D NMR, and ESI-MS spectral data. Seven new oleanane- and ursane-type triterpenoids (1-7) were identified in S. grossheimii. The structures of 1-7 were characterized as; 2α-hydroxy-3ß-acetoxy-olean-9(11),12-diene (1), 2α-acetoxy-3ß-hydroxy-olean-9(11),12-diene (2), 3ß-acetoxy-olean-18-ene,2α,11α-diol (3), 2α-hydroxy-3ß-acetoxy-urs-9(11),12-diene (4), 2α-acetoxy-3ß-hydroxy-urs-9(11),12-diene (5), 2α,3ß-diacetoxy-urs-12-ene-11α,20ß-diol (6), 2α,3ß-diacetoxy-urs-9(11),12-diene-20ß-ol (7). Triterpenoids (2, 5, and 7) were intramolecular transesterification or dehydration products of their corresponding isomers or allylic alcohol in the C rings, respectively, produced in-situ during NMR spectroscopy. Virtual screening of 1-7 was performed with molecular docking analysis to identify the potential SARS-CoV-2 and α-glucosidase inhibitors using the smina molecular docking algorithm. The best binding energy values (kcal/mol) against COVID-19 main protease Mpro were calculated for 6 (-8.77) and 7 (-8.68), and the higher binding affinities toward human α-glucosidase were obtained for 2 (-9.39) and 6 (-8.63). This study suggests S. grossheimii as a rich source of bioactive triterpenoids and introduces new natural compounds. Considering the high binding energy values of 2, 6, and 7, these structures could be candidates for anti-COVID-19 and antidiabetic drug development in the future.

Anti-hyperuricemic bioactivity of Alstonia scholaris and its bioactive triterpenoids in vivo and in vitro.

ETHNOPHARMACOLOGY RELEVANCE: One folk use of Alstonia scholaris (L.) R. Br. in "Dai" ethno-medicine system is to treat gouty arthritis, which might be caused by hyperuricemia, but anti-hyperuricemic investigation of A. scholaris were rarely reported. AIM OF THE STUDY: To verify anti-hyperuricemic property of A. scholaris, and explore its bioactive compounds in vivo and in vitro. MATERIALS AND METHODS: The anti-hyperuricemic bioactivity of the non-alkaloids fraction and compounds were evaluated with potassium oxonate (PO) induced hyperuricemia mice model in vivo, and monosodium urate (MSU) induced human renal tubular epithelial cells (HK-2) was selected to test in vitro, respectively, with benzobromarone as the positive control. 11 triterpenoids were isolated by phytochemical methods and their structures were elucidated by spectroscopic analysis and ECD calculation. RESULTS: The non-alkaloids fraction of A. scholaris decreased the serum uric acid (UA) level in mice model significantly at the doses of 100 mg/kg and 200 mg/kg, and then nine ursane- and two oleanane-triterpenoids including four new compounds (1-3 and 10) were isolated from the bioactive fraction, in which compounds 1, 4, 5, 6 and 10 exhibited better anti-hyperuricemic tendency in vitro by promoting the excretion of UA in MSU-induced HK-2 cell model at a concentration of 5 µM. Furthermore, compounds 1 and 4 were proved to reduce the serum UA level in mice significantly at 5 mg/kg in vivo. CONCLUSIONS: The results supported the traditional use of A. scholaris in treating gouty arthritis, and also provided new bioactive triterpenoids for further chemical and pharmacological investigation.

Terpenoids with α-glucosidase inhibitory activity from Rhododendron minutiflorum Hu.

Five undescribed triterpenoids, two unusual omphalane-type sesquiterpenoids together with twenty-five known compounds were isolated from the leaves and stems of Rhododendron minutiflorum Hu. The absolute configurations of 1-3 and 6 were established by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD). Compounds 6-7 feature the rare omphalane-type sesquiterpene skeleton and are verified by single-crystal X-ray diffraction analysis for the first time. In the biological activity assay, most of the triterpenoids have different degrees of inhibitory effects on α-glucosidase, with IC50 values ranging from 6.97 to 229.3 µM (the positive control drug acarbose has an IC50 value of 3.07 × 10-3 µM). Structure and activity relationship (SAR) study reveals that the oxidation degrees of C-3, C-8, or C-11 to C-13 of the ursane-type triterpenoid influence the inhibitory activity dramatically.

Allobetulone rearrangement to l8αH,19ßH-ursane triterpenoids with antiviral activity.

Allobetulone E-ring rearrangement under treating with HClO4 in Ac2O under reflux afforded new triterpenoids: 3,28-diacetoxy-21-acetyl-2(3),20(21)-18α,19ßH-ursandiene 3 and 3,28-diacetoxy-2(3),18(19)-oleandiene 4. 18α,19ßH-Ursanes were transformed at A- and E-rings into indolo- and bis-furfurylidene 7 derivatives. Structure elucidation was performed using COSY, NOESY, HSQC and HMBC experiments, and X-Ray analysis for 3. The potential of newly obtained 18α,19ßH-ursanes was evaluated against HCMV and HPV-11, the NCI-60 cancer cell panel and inhibition of α-glucosidase. All of the compounds have shown viral inhibition towards HCMV compared to standard drug Acyclovir. 3ß-Acetoxy-21ß-acetyl-20ß,28-epoxy-18α,19ßН-ursane 1 showed moderate activity (EC50 4.87 µM) towards the HCMV-resistant isolate (GDGr K17) compared to standard drug Cidofovir and was four times more potent than Ganciclovir. Compound 7 inhibited the cell growth of the three melanoma and one colon cancer cell. 3-Oxo-21ß-acetyl-20ß,28-epoxy-18α,19ßН-ursane 5 and compound 7 inhibited α-glucosidase with IC50 28.0 µM and 4.0 µM being from 6 to 44 times more active than acarbose.

Ursane-Type Triterpenes, Phenolics and Phenolic Derivatives from Globimetula braunii Leaf.

Globimetula braunii is a hemi-parasitic plant used in African ethnomedicine for the management of microbial infections, rheumatic pain and tumors amongst others. We report the isolation and characterization of eight compounds with their antioxidant and antimicrobial activities. The air-dried powdered leaf was macerated in EtOH/H20 (4:1). The extract was solvent-partitioned into n-hexane, EtOAc, n-BuOH and aqueous fractions. The fractions were screened for their antioxidant properties, using DPPH, FRAP, TAC and FIC assays. Antimicrobial analysis was performed using the micro-broth dilution method. The active EtOAc fraction was purified for its putative compounds on a repeated silica gel column chromatography monitored with TLC-bioautography. The isolated compounds were characterized using spectroscopic methods of UV, FT-IR, NMR and MS. Eight compounds (1-8) were isolated and characterized as 13,27-cycloursane (1), phyllanthone (2), globraunone (3), three phenolics: methyl 3,5-dihydroxy-4-methoxybenzoate (4), methyl 3-methyl-4-hydroxybenzoate (5) and guaiacol (6), as well as two phenol derivatives: 4-formaldehyde phenone (7) and 6-methoxy-2H-inden-5-ol (8). The study identified 4 and 6 as natural antioxidant compounds with potential as antimicrobial agents.

New Polyesterified Ursane Derivatives from Leaves of Maesa membranacea and Their Cytotoxic Activity.

Maesa membranacea A. DC. (Primulaceae) is a plant species that has been frequently used by practitioners of the traditional ethnobotany knowledge from northern and central Vietnam. However, the chemical constituents of the plant remained unknown until recently. Chromatographic separation of a chloroform-soluble fraction of extract from leaves of M. membranacea led to the isolation of two new polyesterified ursane triterpenes (1-2) and two known apocarotenoids: (+)-dehydrovomifoliol (3) and (+)-vomifoliol (4). The chemical structures of the undescribed triterpenoids were elucidated using 1D and 2D MNR and HRESIMS spectral data as 2α,6ß,22α-triacetoxy-11α-(2-methylbutyryloxy)-urs-12-ene-3α,20ß-diol (1) and 2α,6ß,22α-triacetoxy-urs-12-ene-3α,11α,20ß-triol (2). The newly isolated triterpenoids were tested for their cytotoxic activity in vitro against two melanoma cell lines (HTB140 and A375), normal skin keratinocytes (HaCaT), two colon cancer cell lines (HT29 and Caco-2), two prostate cancer cell lines (DU145 and PC3) and normal prostate epithelial cells (PNT-2). Doxorubicin was used as a reference cytostatic drug. The 2α,6ß,22α-triacetoxy-11α-(2-methylbutyryloxy)-urs-12-ene-3α,20ß-diol demonstrated cytotoxic activity against prostate cancer cell lines (Du145-IC50 = 35.8 µg/mL, PC3-IC50 = 41.6 µg/mL), and at a concentration of 100 µg/mL reduced viability of normal prostate epithelium (PNT-2) cells by 41%.

Two new cytotoxic ursane triterpenoids from the aerial parts of Salvia urmiensis Bunge.

Bioassay-guided fractionation of a dichloromethane extract of the aerial parts of Salvia urmiensis, an endemic plant species of Iran, led to the isolation of two new cytotoxic ursane triterpenoids, Salvurmin A and Salvurmin B. Their structures were elucidated by a combination of 1D and 2D NMR, HR-ESI-MS, IR and UV analysis. Cytotoxicity of the above-mentioned compounds were evaluated against two human cancerous cell lines (SW1116, MCF-7). IC50 values for Salvurmin A and Salvurmin B on colon cancer cell line (SW1116) were 41.6 ± 2.6 and 23.2 ± 0.4 µM respectively, in comparison to cisplatin as control positive. In addition, these two compounds exhibited cytotoxic activity on breast cancer cell line (MCF-7) with an IC50 of 54.2 ± 5.3 and 40.2 ± 3.1 µM for Salvurmin A and Salvurmin B, respectively. The cytotoxic activities of these two compounds present a promising potential for the future investigation on this endemic species of Salvia.

Ulmoidol, an unusual nortriterpenoid from Eucommia ulmoides Oliv. Leaves prevents neuroinflammation by targeting the PU.1 transcriptional signaling pathway.

Chronic neuroinflammation is closely associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). In the current study, 13 anti-neuroinflammatory compounds were isolated from Eucommia ulmoides Oliv. leaves. Among these compounds, trans-sinapaldehyde (6), 3',4',5,7-tetrahydroxy-3-methylflavone (7), and amarusine A (13) were isolated from E. ulmoides leaves for the first time. The ursane-type C29-triterpenoid, ulmoidol (ULM, 9), significantly inhibited the production of proinflammatory mediators and reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, ULM inhibited the cluster of differentiation 14 (CD14)/Toll-like receptor 4 (TLR4) signaling pathway and consequently limited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Notably, electrophoretic mobility shift assay (EMSA) and molecular docking analyses indicated that ULM could prevent PU box binding-1 (PU.1) from binding to DNA, suggesting that PU.1 might be a potential ULM target. In conclusion, ULM alleviates neuroinflammatory responses in microglia, which could be partly explained by its targeting of PU.1 and the resulting suppression of the TLR4/MAPK/NF-κB signaling pathways. These results suggested that ULM may have therapeutic potential as an agent for treating neuroinflammation-related neurodegenerative diseases.

The Identification of New Triterpenoids in Eucalyptus globulus Wood.

Eight polyhydroxy triterpenoid acids, hederagenin, (4α)-23-hydroxybetulinic acid, maslinic acid, corosolic acid, arjunolic acid, asiatic acid, caulophyllogenin, and madecassic acid, with 2, 3, and 4 hydroxyl substituents, were identified and quantified in the dichloromethane extract of Eucalyptus globulus wood by comparing their GC-retention time and mass spectra with standards. Two other triterpenoid acids were tentatively identified by analyzing their mass spectra, as (2α)-2-hydroxybetulinic acid and (2α,4α)-2,23-dihydroxybetulinic acid, with 2 and 3 hydroxyl substituents. Two MS detectors were used, a quadrupole ion trap (QIT) and a quadrupole mass filter (QMF). The EI fragmentation pattern of the trimethylsilylated polyhydroxy structures of these triterpenoid acids is characterized by the sequential loss of the trimethylsilylated hydroxyl groups, most of them by the retro-Diels-Alder (rDA) opening of the C ring with a π-bond at C12-C13. The rDA C-ring opening produces ions at m/z 320 (or 318) and m/z 278 (or 277, 276, 366). Sequential losses of the hydroxyl groups produce ions with m/z from [M - 90] to [M - 90*y], where y is the number of hydroxyl substituents present (from 2 to 4). Moreover, specific cleavage in ring E was observed, passing from m/z 203 to m/z 133 and conducting other major fragments such as m/z 189.

New triterpenoid saponins from the leaves of Ilex chinensis and their hepatoprotective activity.

Seven new triterpenoid saponins, including five ursane-type saponins, ilexchinenosides R-V (1-5), and two oleanane-type saponins, ilexchinenosides W-X (6-7), with four known triterpenoid saponins (8-11) were isolated from the leaves of Ilex chinensis. Their structures were elucidated by comprehensive spectroscopic 1D and 2D NMR and HR-ESI-MS data. Their sugar moieties were determined by HPLC analysis compared with standards after hydrolysis and derivatization. Compounds 1, 2, 4, 9 and 10 exhibited potential hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell injury in vitro.