Triterpenoid Esters Research Articles

The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer.

NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects of NRF2 activation remain poorly understood in the context of cancer. To test CDDO-Me in a murine model of established lung cancer, tumor-bearing wildtype (WT) and Nrf2 knockout (KO) mice were treated with 50-100 mg CDDO-Me/kg diet, alone or combined with carboplatin/paclitaxel (C/P) for 8-12 weeks. CDDO-Me decreased tumor burden in an Nrf2-dependent manner. The combination of CDDO-Me plus C/P was significantly (p < 0.05) more effective than either drug alone, reducing tumor burden by 84% in WT mice. CDDO-Me reduced the histopathological grade of WT tumors, with a significantly (p < 0.05) higher proportion of low-grade tumors and a lower proportion of high-grade tumors. These changes were augmented by combination with C/P. CDDO-Me also protected WT mice from C/P-induced toxicity and improved macrophage and T cell phenotypes in WT mice, reducing the expression of CD206 and PD-L1 on macrophages, decreasing immunosuppressive FoxP3+ CD4+ T cells, and increasing activation of CD8+ T cells in a Nrf2-dependent manner.

Abstract 2028: The triterpenoid CDDO-Methyl ester requires Nrf2 to decrease lung tumor burden and to protect against the toxicity of chemotherapy in experimental lung cancer

Abstract The NRF2 cytoprotective pathway, a drug target for many inflammation-related diseases, regulates immune cell function. While the anti-inflammatory nature of NRF2 activation protects healthy cells from malignant transformation, cancer cells can utilize the pathway to promote resistance to anti-cancer drugs. Up to 30% of human lung adenocarcinomas acquire mutations in either NFE2L2 or its negative regulator KEAP1 which result in constitutive activation of the NRF2 pathway. However, despite our knowledge of the important immunomodulatory effects of NRF2, these effects are not well characterized in the context of cancer. With NRF2 activators now approved for clinical use, it is critical to understand the impact of these drugs in cancer. Triterpenoids including CDDO-methyl ester (CDDO-Me, also known as bardoxolone methyl) are potent pharmacological NRF2 activators with demonstrated anti-cancer activity in preclinical models. In an early-stage preclinical model of lung cancer, CDDO-Me significantly decreased tumor burden in a dose- and Nrf2-dependent manner and improved immune signatures within the tumor microenvironment. However, most human lung cancers are not diagnosed until more advanced stages. To test CDDO-Me in an established tumor intervention model, lung tumors were initiated with vinyl carbamate in A/J WT and Nrf2 knockout (KO) mice. Tumors were allowed to develop for 8 weeks post initiation, after which mice were fed either a vehicle control diet or CDDO-Me (50-100 mg/kg of diet) for an additional 8-12 weeks, alone or in combination with carboplatin and paclitaxel (C/P) at 50 mg/kg and 15 mg/kg, respectively, by IP injection every other week. CDDO-Me significantly (p &amp;lt; 0.05) decreased surface lung tumor counts 35-71% in a Nrf2-dependent manner, and C/P significantly (p &amp;lt; 0.001) reduced tumor burden 53-59% regardless of Nrf2 status. The combination of CDDO-Me + C/P reduced tumor burden in WT lungs by 84% (p &amp;lt; 0.05), more than either agent alone. Nrf2 KO mice had an approximately two-fold increase (p &amp;lt; 0.001) of surface tumors compared to WT mice in both studies, regardless of treatment. C/P reduced tumor burden similarly in Nrf2 WT and Nrf2 KO mice. Interestingly, the combination of CDDO-Me + C/P increased T cell infiltration into the lungs of WT mice, but this change was not observed in groups treated with either agent alone. Importantly, CDDO-Me did not decrease the efficacy of C/P but protected WT mice from mortality and weight loss and lowered white and red blood cell counts. These studies suggest that NRF2 activation in advanced lung cancers can still decrease tumor burden by favorably modulating the immune microenvironment and, importantly, complements the anti-tumor efficacy of conventional chemotherapy while decreasing drug toxicity. Citation Format: Jessica Ann Moerland, Karen T. Liby. The triterpenoid CDDO-Methyl ester requires Nrf2 to decrease lung tumor burden and to protect against the toxicity of chemotherapy in experimental lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2028.

Triterpenoid esters from Capparis erythrocarpos (Isert), Capparaceae, root bark ameliorates CFA-induced arthritis

The root bark of Capparis erythrocarpos (CERB) is employed to treat rheumatoid arthritis (RA) in Africa, particularly in Ghana. However, there was no isolation and characterization of the bioactive constituents responsible for the pharmacological actions of this plant. The aim of this study is to isolate, characterize and evaluate the anti-arthritic activity of the constituents of CERB. CERB was soxhleted and partitioned into various fractions. The constituents were isolated using column chromatography and characterized by 1D and 2D NMR spectroscopy. The precise carboxylic acid residues of the esters were determined using saponification, derivatization and GC–MS analysis. Anti-arthritic activity was evaluated in the CFA-induced arthritic model. Two triterpenoid esters namely, sitosterol 3-hexadecanoate or sitosterol 3-palmatate (1) and sitosterol 3-tetradecanoate or sitosterol 3-myristate (2) in addition to beta sitosterol (3) were isolated and characterized. Compounds 1 and 2 administered at 3 µmol/kg (p.o.) produced anti-inflammatory activity (P < 0.0001) of 31.02 and 39.14% respectively, in addition to arthritic score index (P < 0.0001) of 1.600 ± 0.2449 and 1.400 ± 0.2449 against CFA-induced arthritis which are equivalent to those of the standard drug, diclofenac sodium (DS), 3 µmol/kg (p.o.), (30.79% anti-inflammatory activity and 1.800 ± 0.3742 arthritic score index). The compounds produced similar anti-inflammatory effects as DS. Also, radiographical and histopathological studies showed that, the compounds and DS protected against bone destruction, inflammatory cells invasion into interstitial spaces and synovial liner hyperplasia of the joints. This is the first study to report the characterization of the constituents of C. erythrocarpos in addition to anti-arthritic activity of sitosterol 3-palmatate and sitosterol 3-myristate. These results provide the missing link between the chemistry and the pharmacological activities of C. erythrocarpos. The isolates also offer a different class of molecule which could provide alternative treatment for RA.

Antioxidant, antimicrobial and antityrosinase activities of phytochemicals from the leaves of Globimetula braunii (Engler) Van Tiegh (Loranthaceae)

ABSTRACT. Herbal preparations of Globimetula braunii leaves are used in tropical African countries for the treatment of several illnesses. A preliminary study of the leaf extracts of Globimetula braunii has confirmed the antioxidant, antibacterial, biochemical and toxicological potency of the plant. The leaf extracts were subjected to bioactivity guided fractionation that led to the isolation of the active compounds. Antioxidant, antityrosinase and antimicrobial inhibitory activities of the isolated compounds were evaluated. Structural elucidations of the isolated compounds were carried out spectroscopically, including the use of 1D/2D nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) spectroscopies and mass spectrometry. Results indicated that quercetin (15) isolated from ethyl acetate fraction exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) scavenging capacity and also showed the highest ferric reducing antioxidant potential (FRAP) equivalent value. Quercetin (15) and dodoneine (14) displayed the highest tyrosinase inhibition activity with IC50 value of 0.12±0.32 mM and 0.19±0.20 mM, respectively. All the isolated compounds showed weak to not active in the antimicrobial inhibition assay. The findings in this report have revealed the antioxidant and antityrosinase potential of Globimetula braunii and thus supporting their traditional uses.&#x0D; &#x0D; KEY WORDS: Globimetula braunii, Antioxidant, Antityrosinase, Antimicrobial, Triterpenoid esters, Dodoneine&#x0D; &#x0D; Bull. Chem. Soc. Ethiop. 2022, 36(2), 387-397. &#x0D; DOI: https://dx.doi.org/10.4314/bcse.v36i2.12

Phenylpropanoid-conjugated pentacyclic triterpenoids from the whole plants of Leptopus lolonum induced cell apoptosis via MAPK and Akt pathways in human hepatocellular carcinoma cells

Our present and previous phytochemical investigations on Leptopus lolonum have resulted in the isolation of almost 30 phenylpropanoid-conjugated pentacyclic triterpenoids (PCPTs). During the continuous study on PCPTs, this kind of triterpenoid ester is considered as a natural product with low toxicity because of it’s widely distribution in natural plants and edible fruits including kiwi fruit, durian, jujube, pawpaw, apple and pear. In the present work, we report the isolation, structural elucidation and cytotoxic evaluation of four new PCPTs (1–4) which obtained from L. lolonum. In addition, the possible biosynthesis pathway for 28-norlupane triterpenoid and potent effect of phenylpropanoid moiety for increasing the cytotxic effect of triterpenoids were also discussed. Among these compounds, compound 1 exhibited the highest cytotoxic effect on HepG2 cells with IC50 value of 11.87 μM. Further flow cytometry and western blot analysis demonstrated that 1 caused G1 cell cycle arrest by up-regulated the expression of phosphorylated p53 protein in HepG2 cells and induced cell apoptosis via MAPK and Akt pathways. These results emphasized the potential of PCPTs as lead compounds for developing anti-cancer drugs.

Metabolite pattern in root nodules of the actinorhizal plant Casuarina equisetifolia

Casuarina equisetifolia L. (Casuarinaceae), an actinorhizal plant, exhibits mutualistic symbiosis with Frankia and promotes nitrogen fixation in root nodules. While the exchange of metabolites between host plant and microsymbiont is well understood in legume symbioses, the situation in the symbiosis between nitrogen-fixing Frankia and actinorhizal plants is less clear. In this study, a metabolomic approach was applied to root nodules of mature C. equisetifolia trees, leading to the identification of an undescribed taraxerane-type triterpenoid ester, 3-O-dihydrocoumaroyl β-taraxerol, along with twelve known compounds. An abundant component was tyramine with a content of 2.76 ± 0.315 mg/g FW in mature nodules. Tyramine specifically and abundantly accumulated in mature nitrogen-fixing nodules compared to senescent nodules, stems, leaves, and seeds. In addition, the potential function of tyramine was preliminarily examined and discussed.

Study on chemical constituents of Wedelia trilobata

A new taraxer-based triterpenoid ester, taraxer-14-en-30-al-3β-O-palmitate(1), was isolated from the whole plant of Wedelia trilobata, along with six known compounds, ent-kaur-16-en-19-oic acid(2), 16α-hydroxy-ent-kauran-19-oic acid(3), tara-xerol(4), β-amyrin(5), 1β-acetoxy-4α, 9α-dihydroxy-6β-isobutyroxyprostatolide(6), and stigmasterol(7). Their structures were elucidated with use of a combination of spectroscopic techniques(IR, HR-ESI-MS, 1 D, 2 D NMR data) and chemical methods.

Triterpenoids and steroids isolated from Anatolian Capparis ovata and their activity on the expression of inflammatory cytokines

Context Capparis L. (Capparaceae) is grown worldwide. Caper has been used in traditional medicine to treat various diseases including rheumatism, kidney, liver, stomach, as well as headache and toothache. Objective To isolate and elucidate of the secondary metabolites of the C. ovata extracts which are responsible for their anti-inflammatory activities. Materials and methods Buds, fruits, flowers, leaves and stems of C. ovata Desf. was dried, cut to pieces, then ground separately. From their dichloromethane/hexane (1:1) extracts, eight compounds were isolated and their structures were elucidated by NMR, mass spectroscopic techniques. The effects of compounds on the expression of inflammatory cytokines in SH-SY5Y cell lines were examined by qRT-PCR ranging from 4 to 96 µM. Cell viability was expressed as a percentage of the control, untreated cells. Results This is a first report on isolation of triterpenoids and steroids from C. ovata with anti-inflammatory activity. One new triterpenoid ester olean-12-en-3β,28-diol, 3β-pentacosanoate (1) and two new natural steroids 5α,6α-epoxycholestan-3β-ol (5) and 5β,6β-epoxycholestan-3β-ol (6) were elucidated besides known compounds; oleanolic acid (2), ursolic acid (3), β-sitosterol (4), stigmast-5,22-dien-3β-myristate (7) and bismethyl-octylphthalate (8). mRNA expression levels as EC10 of all the tested seven genes were decreased, particularly CXCL9 (19.36-fold), CXCL10 (8.14-fold), and TNF (18.69) by the treatment of 26 µM of compound 1 on SH-SY5Y cells. Discussion and conclusions Triterpenoids and steroids isolated from C. ovata were found to be moderate-strong anti-inflammatory compounds. Particularly, compounds 1 and 3 were found to be promising therapeutic agents in the treatment of inflammatory and autoimmune diseases.

Betulin-related esters from birch bark tar: Identification, origin and archaeological significance

Birch bark tar, an organic material frequently encountered during archaeological excavations, has been identified from its lipid composition on the cracks of a ceramic dated to the late Neolithic. Lipids of this black substance were dominated by a characteristic triterpenoid assemblage of lupane-related triterpenoids from birch bark, together with their thermal degradation products formed during preparation of the tar. Among the latter, four main series of unusual triterpenoid esters have been detected and were postulated to correspond to esters of Δ 2-betulin and Δ2-dihydrobetulin based on their mass spectra and hydrolysis experiments. Their conclusive identification has been achieved by synthesis of reference compounds. These compounds most likely originate from the esterification between triterpenoid alcohols related to betulin and fatty acids from suberin formed upon heating of birch bark tar. They could be considered as markers of intense heating during birch bark tar preparation using the “single pot” procedure.

Terpenoids and phenolics of Micromeria persica

Phytochemical investigation of the aerial parts of Micromeria persica led to the isolation of a new oleane type triterpenoid ester (1), together with six known compounds 2–7), comprising one phenyl ethanoid ester, one glycosylated flavonoid, two triterpenoids, and two steroids. Their structures were elucidated by interpretation of their one-dimensional and two-dimensional NMR spectra and completed by the analysis of the HRESIMS data. Compounds 1 and 3 were evaluated for their cytotoxic feature against human breast adenocarcinoma cell line (MDA-MB231) and human prostate cancer cell line (DU145). However, they did not show positive effect (IC50 > 75µM).

Globrauneine A–F: six new triterpenoid esters from the leaves of Globimetula braunii

Phytochemical study was conducted on the leaves of Globimetula braunii which is a hemi parasitic plant belonging to the family Loranthaceae. Extraction was carried out using cold extraction method with increasing polarity of solvents i.e n-hexane, CH2Cl2 and MeOH. The components were separated by chromatographic technique and the structures of the compounds were elucidated by extensive spectroscopic analyses including MS, FTIR, 1D and 2D NMR, HRMS and chemical methods. Six new pentacyclic triterpenoid esters named as globrauneine A (1), globrauneine B (2), globrauneine C (3), globrauneine D (4), globrauneine E (5), and globrauneine F (6), together with six known compounds (7 – 12) were successfully isolated from the leaves of G. braunii growing on Piliostigma thonningii. These results depict a substantial support to the chemotaxonomy of the genus Globimetula.

A HPLC-MS method for profiling triterpenoid acids and triterpenoid esters in Osmanthus fragrans fruits.

Triterpenoids, as an important family of plant secondary metabolites, have important biological activities associated with health and disease prevention. In this work, we proposed a HPLC-MS method for profiling multiple groups of triterpenoid acids and triterpenoid esters differing only in one position of the hydroxyl or methyl group in O. fragrans fruits. A total of thirty-one compounds were identified, and twenty-seven components were discovered in O. fragrans fruits for the first time. The HPLC-MS profiling method was applied in the analysis of the triterpenoids of O. fragrans flowers, and the time courses of triterpenoids of O. fragrans fruits.

Chemical constituents of Scurrula parasitica

A new triterpenoid ester, 7β-hydroxyl-hop-22(29)-en-3β-O-palmitate (1), was isolated from the stems and leaves of Scurrula parasitica parasitic on Nerium indicum, along with nine known compounds, uvaol (2), 3-epi-ursolic acid (3), 3β-hydroxyl-hop-22(29)-ene (4), 3β, 15α-dihydroxyl-lup-20(29)-ene (5), lup-20(29)-en-3-O-α-D-glucoside (6), stigmasterol-3-O-β-D-glucoside (7), digitoxin-3-O-α-D-glucoside (8), behenic acid (9), octacosyl alcohol (10). Their structures were elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, and HMBC) and HR-ESI-MS analyses. Compounds 2-10 were isolated from this plant for the first time.

Caffeoyl Triterpenoid Esters as Potential Anti-ischemic Stroke Agents from Celastrus orbiculatus.

Three new triterpenoids, celastrusins A-C (1-3), together with 3-O-caffeoyl-α-amyrin (4) were isolated from the root bark of Celastrus orbiculatus. Their structures were identified by spectroscopic analysis, X-ray crystallography using Cu Kα radiation, and the comparison of both observed and reported spectroscopic data. An in vitro bioassay revealed that the caffeoyl triterpenoid esters 1, 3, and 4 possess neuroprotective effects against oxygen-glucose deprivation (OGD) induced SH-SY5Y cell damage. Further animal studies indicated that compound 1 significantly reduced brain infarction after transient middle cerebral artery occlusion (MCAO) in rats using a 10 mg/kg (i.v.) dose.

Composition of the epicuticular waxes coating the adaxial side of Phyllostachys aurea leaves: Identification of very-long-chain primary amides

The present study presents comprehensive chemical analyses of cuticular wax mixtures of the bamboo Phyllostachys aurea. The epicuticular and intracuticular waxes were sampled selectively from the adaxial side of leaves on young and old plants and investigated by gas chromatography-mass spectrometry and flame ionization detection. The epi- and intracuticular layers on young and old leaves had wax loads ranging from 1.7 μg/cm2 to 1.9 μg/cm2. Typical very-long-chain aliphatic wax constituents were found with characteristic chain length patterns, including alkyl esters (primarily C48), alkanes (primarily C29), fatty acids (primarily C28 and C16), primary alcohols (primarily C28) and aldehydes (primarily C30). Alicyclic wax components were identified as tocopherols and triterpenoids, including substantial amounts of triterpenoid esters. Alkyl esters, alkanes, fatty acids and aldehydes were found in greater amounts in the epicuticular layer, while primary alcohols and most terpenoids accumulated more in the intracuticular wax. Alkyl esters occurred as mixtures of metamers, combining C20 alcohol with various acids into shorter ester homologs (C36C40), and a wide range of alcohols with C22 and C24 acids into longer esters (C42C52). Primary amides were identified, with a characteristic chain length profile peaking at C30. The amides were present exclusively in the epicuticular layer and thus at or near the surface, where they may affect plant-herbivore or plant-pathogen interactions.

Phytochemical Investigations of Methanol Leaf Extracts of Randia spinosa Using Column Chromatography, HPTLC and GC-MS

The present study was aimed to identify phytochemical presence in leaves of Randia spinosa using hexane, chloroform, ethanol, methanol and distilled water for extraction. Among these solvents, methanol have shown important phytochemicals in qualitative method. Further, column chromatography has been carried out for the partial purification of methanol extract by sequential elution with hexane, ethyl acetate and methanol as eluents. The methanol extract of HPTLC study shows the significant phytochemicals. GC-MS result of ethyl acetate extraction of leaves shown the presence of triterpenoid esters, cinnamate, naphthalene, phenolic compounds mainly BHT and methanol fraction has shown the presence of triterpenoid esters, amines and coumarins mainly, 5a-methoxy-9a-methyl-3-(1-propenyl) perhydro-pyrano[4,3-b]benzopyran

ChemInform Abstract: A Hydroxylated Lupeol‐Based Triterpenoid Ester Isolated from the Scurrula parasitica Parasitic on Nerium indicum

Abstractisolation, structure elucidation and cytotoxic activity of the new terpenoid ester (I) and sixteen known compounds

A Hydroxylated Lupeol‐Based Triterpenoid Ester Isolated from the Scurrula parasitica Parasitic on Nerium indicum

Abstract(3β,7β)‐7‐Hydroxylup‐20(29)‐en‐3‐yl hexadecanoate (1), a new lupeol‐based triterpenoid ester, along with sixteen known compounds, 7β,15α‐dihydroxylup‐20(29)‐ene‐3β‐O‐palmitate (2), lupeol palmitate (3), lupeol (4), 3‐oxolup‐20(29)‐ene (5), ursolic acid (6), cycloeucalenol (7), stigmasterol (8), β‐sitosterol (9), β‐daucosterol (10), quercetin (11), quercetin 3‐O‐α‐L‐arabinoside (12), quercetin 3‐O‐α‐L‐rhamnoside (13), catechin (14), gitoxigenin 3‐O‐α‐L‐rhamnoside (15), gitoxigenin 3‐O‐α‐D‐glucoside (16), and digitoxigenin 3‐O‐α‐L‐rhamnoside (17), was isolated from the leaves of the Southern China mistletoe, Scurrula parasitica Linn parasitic on Nerium indicum Mill. Their structures were elucidated by spectroscopic analyses, including 2D‐NMR techniques. Cytotoxic activities of compounds 1–7 and 11–17 were evaluated against three cancer cell lines, PANC‐1, HL‐60, and SGC‐7901, revealing that compounds 4, 6, 11, and 15–17 exhibited effective cytotoxicities, while others were inactive. A structureactivity relationship study of compounds 1–5 indicated that the 3‐OH group in lupeol‐based triterpenoids is essential for antitumor activity.

Chemical constituents from Glochidion wrightii Benth.

Phytochemical investigation of the leaves and stems of Glochidion wrightii Benth. led to the isolation of one new triterpenoid ester, 3 β -tetradecanoyloxy-1 β -hydroxylup-20(29)-ene ( 1 ), and twenty-nine known compounds ( 2 – 30 ), including (3 β ,16 β )-lup-20(30)-ene-3,16,29-triol ( 8 ) reported as a natural product for the first time. Their structures were identified by spectroscopic analysis and by comparison of their spectral data with those reported in the literature. The chemotaxonomic analysis is concordant with the newest molecular phylogenetic and morphological classifications that the genus Glochidion is deeply embedded within the large Phyllanthus . ► One new triterpenoid ester 1 was yielded from Glochidion wrightii . ► Compound 8 was reported as a natural product for the first time. ► Twenty-one compounds were obtained from the genus Glochidion for the first time. ► The genus Glochidion is embedded within Phyllanthus from a chemotaxonomic view.

A new triterpenoid ester from Lobelia sessilifolia

One novel triterpenoid ester, oleanol 28-aldehyde 3-O-β-palmitate (1), was isolated from the aerial part of Lobelia sessilifolia Lamb. along with seven known compounds, namely two triterpenoid esters (2, 3), one sterol (4), two coumarins (5, 6), and two triterpenes (7, 8). The structure of 1 was established on the basis of spectroscopic and chemical data.