Cucurbitane-type Triterpenoids Research Articles

New cucurbitane-type triterpenoid glucosides from the tubers of Hemsleya amabilis with anti-tumor activity

Two new cucurbitane-type triterpenoid glucosides, 3β,11α-dihydroxycucurbita-5,24(E)-diene-3,26-glucosides (1) and 3β,11α-dihydroxycucurbita-5,24(Z)-diene-3,27-glucosides were isolated from the tubers of Hemsleya amabilis. Their structures were elucidated by various spectroscopic techniques including IR, HRESIMS, 1D and 2D NMR. The two compounds were evaluated for their anti-tumor activity against HeLa and HepG-2 cell lines, and both displayed moderate anti-tumor activity towards HeLa cell lines with IC50 values of 9.8 and 15.7 μM, respectively.

Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells.

The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant Momordica balsamina and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells.

Plant-derived isoprenoid sweeteners: recent progress in biosynthetic gene discovery and perspectives on microbial production.

Increased public awareness of negative health effects associated with excess sugar consumption has triggered increasing interest in plant-derived natural sweeteners. Steviol glycosides are a group of highly sweet diterpene glycosides contained in the leaves of stevia (Stevia rebaudiana). Mogrosides, extracted from monk fruit (Siraitia grosvenorii), are a group of cucurbitane-type triterpenoid glycosides. Glycyrrhizin is an oleanane-type triterpenoid glycoside derived from the underground parts of Glycyrrhiza plants (licorice). This review focuses on the natural isoprenoid sweetening agents steviol glycosides, mogrosides, and glycyrrhizin, and describes recent progress in gene discovery and elucidation of the catalytic functions of their biosynthetic enzymes. Recently, remarkable progress has been made in engineering the production of various plant-specialized metabolites in microbial hosts such as Saccharomyces cerevisiae via the introduction of biosynthetic enzyme genes. Perspectives on the microbial production of plant-derived natural sweeteners are also discussed.

Cucurbitane Triterpenoids from the Fruits of Momordica Charantia Improve Insulin Sensitivity and Glucose Homeostasis in Streptozotocin-Induced Diabetic Mice.

Momordica charantia (M. charantia) has antidiabetic effects, and cucurbitane-type triterpenoid is one of the compounds of M. charantia. This study aims to investigate whether the new cucurbitane-type triterpenoids affect insulin sensitivity both in vitro and in vivo, and the underlying mechanisms. Four compounds (C1-C4) isolated from the ethanol extract of M. charantia enhance glucose uptake in C2C12 myotubes via insulin receptor substrate-1 (IRS-1) rather than via adenosine monophosphate-activated protein kinase. The most potent, compound 2 (C2), significantly increases the activation of IRS-1 and downstream signaling pathways, resulting in glucose transporter 4 translocation. Furthermore, these C2-induced in vitro effects are blocked by specific signal inhibitors. We further evaluate the antidiabetic effect of C2 using a streptozotocin (STZ)-induced diabetic mouse model. Consistent with in vitro data, treatment with C2 (1.68 mgkg-1 ) significantly decreases blood glucose level and enhances glycogen storage in STZ-injected mice. These effects appear to be mediated by the IRS-1 signaling pathway in skeletal muscle, not in adipose and liver tissues, suggesting that C2 improves hyperglycemia by increasing glucose uptake into skeletal muscle. Our findings demonstrate that the new cucurbitane-type triterpenoids have potential for prevention and management of diabetes by improving insulin sensitivity and glucose homeostasis.

Antiaging of Cucurbitane Glycosides from Fruits of Momordica charantia L.

Methanol extracts of Momordica charantia L. fruits are extensively studied for their antiaging activities. A new cucurbitane-type triterpenoid (1) and nine other known compounds (2–10) were isolated, and their structures were determined according to their spectroscopic characteristics and chemical derivatization. Biological evaluation was performed on a K6001 yeast bioassay system. The results indicated that all the compounds extended the replicative lifespan of K6001 yeast significantly. Compound 9 was used to investigate the mechanism involved in the increasing of the lifespan. The results indicated that this compound significantly increases the survival rate of yeast under oxidative stress and decreases ROS level. Further study on gene expression analysis showed that compound 9 could reduce the levels of UTH1 and SKN7 and increase SOD1 and SOD2 gene expression. In addition, it could not extend the lifespan of the yeast mutants of Uth1, Skn7, Sod1, and Sod2. These results demonstrate that compound 9 exerts antiaging effects via antioxidative stress and regulation of UTH1, SKN7, SOD1, and SOD2 yeast gene expression.

Cucurbitane triterpenoids from Momordica charantia L. and their inhibitory activity against α-glucosidase, α-amylase and protein tyrosine phosphatase 1B (PTP1B)

Momordica charantia L. has been widely used in different countries as a functional food source, particularly as a remedy for type 2 diabetes. In the present study, 21 cucurbitane-type triterpenoids, including two new compounds named charantoside IX and X (1−2), were isolated from the extract of M. Charantia L.Their chemical structures were identified by 1D, 2D-NMR and FT-ICR-MS techniques. Three anti-diabetes target assays of all triterpenoids were carried out, with all compounds exhibiting α-glucosidase inhibitory activity. Particularly, compounds 6, 9 and 11 exhibited excellent α-glucosidase inhibitory activity with IC50 values of 10.19, 28.55, and 20.20μM, respectively. Some of the tested isolates showed inhibitory activity against the protein tyrosine phosphatase 1B (PTP1B) and α-amylase, with compound 6 exhibiting the strongest activity against PTP1B. These chemical and biological results indicated that cucurbitane triterpenoids in functional foodsmay represent attractive candidates for regulation of blood glucose levels.

Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia.

The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M. charantia, utilizing diverse chromatographic and spectroscopic techniques. In particular, the 2D structure of 1 was confirmed utilizing the long-range HSQMBC NMR pulse, capable of measuring heteronuclear long-range correlations (4-6JCH). The cucurbitanes were also assessed for their inhibitory activity against PDGF-induced VSMC proliferation. This current study may constitute a basis for developing those chemotypes into sensible pharmacophores alleviating cardiovascular disorders.

Cucurbitane-Type Triterpenoids from Momordica charantia

Two new cucurbitane-type triterpenoids, 7β,23( S)-dimethoxycucurbita-5,24-dien-3β-ol (1) and 3 β-hydroxycucurbita-6,23( E),25-trien-5 β,19-olide (2), and two known cucurbitane-type triterpenoids, 7 β,25-dimethoxycucurbita-5,23( E)-dien-3 β-ol (3) and karavilagenin D (4), were isolated from the fruit pulp of Momordica charantia. Their structures were established by means of 1D and 2D NMR spectra (1H, 13C, COSY, HMQC, HMBC, and NOESY) as well as EI-MS data.

Mogroside IIIE Attenuates LPS-Induced Acute Lung Injury in Mice Partly Through Regulation of the TLR4/MAPK/NF-κB Axis via AMPK Activation.

Acute lung injury (ALI) often leads to high mortality, and there is as yet no effective drug treatment. The present study aimed to investigate protective effects of mogroside IIIE (MGIIIE, a cucurbitane-type triterpenoid from Siraitia grosvenorii Fruits) in experimental ALI and its underlying mechanism. MGIIIE (1, 10 0r 20mg/kg) was orally administered for 1h before a single intratracheal administration of lipopolysaccharide (LPS, 5mg/kg). MGIIIE treatment dose-dependently suppressed pulmonary oedema, pro-inflammatory mediators (IL-1β, IL-6, TNF-α and HMGB1) release and higher MPO activity in lung tissues induced by LPS challenge. Molecular researches showed that mogroside IIIE (20mg/kg) not only increased the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) but suppressed the over-expression of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In addition, MGIIIE also inhibited the activation of MAPKs and nuclear factor κB (NF-κB) signalling in lung tissues from LPS-challenged mice. Similar antiinflammatory effects of MGIIIE were obtained in LPS-treated macrophages. Compound C (a pharmacological AMPK inhibitor) obviously reversed the antiinflammatory effect of MGIIIE in LPS-induced ALI mice. Taken together, AMPK activation plays a crucial role in the antiinflammatory effects of MGIIIE in LPS-induced ALI by down-regulating TLR4/MAPK/NF-κB signalling pathways. Copyright © 2017 John Wiley & Sons, Ltd.

Cucurbitane-Type Triterpenoids from the Blood Glucose-Lowering Extracts of Coccinia indica and Momordica balsamina Fruits.

Context:Few vegetables that are commonly consumed in India as part of diet have been claimed for their antidiabetic potential.Objective:The present study was aimed at evaluating preventive effects of cucurbit vegetables namely, Coccinia indica and Momordica balsamina belonging to family Cucurbitaceae in diabetic hyperglycemia.Materials and Methods:The fruits of M. balsamina and C. indica were extracted with chloroform and fractionated with hexane to prepare an extract rich in moderately polar components. These extracts were used for evaluating the effect of these cucurbits in nicotinamide/streptozotocin-induced type 2 diabetes. Streptozotocin–nicotinamide-induced diabetic animals were orally treated with chloroform extract of fruits (250 mg/kg BW) given daily for a week separately.Results:Both the extracts reduced fasting blood glucose significantly (P < 0.05 versus diabetic control) when estimated on seventh day of treatments. Pretreatment with fruit extracts for 7 days also blunted the OGTT (oral glucose tolerance test) curve. Results indicated that C. indica and M. balsamina fruits possess beneficial effects in diabetes by lowering elevated blood glucose level. Six cucurbitane-type triterpenoids were isolated from bioactive extracts of C. indica ((1-3) and M. balsamina (4-6). The structures of these compounds were elucidated on the basis of spectroscopic data analysis.Conclusion:The study concludes that the inclusion of C. indica and M. balsamina fruits in food can be useful for newly diagnosed diabetic patients or highrisk group of population for glycemic control.SUMMARY“Cucurbitane-type triterpenoids from the blood glucose-lowering extracts of Coccinia indica and M. balsamina fruit” The beneficial effects of chloroform extracts of vegetal cucurbits namely C. indica (Ivy gourd) and M. balsamina (Balsam apple) in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats has been evaluated.The isolation and characterization of six cucurbitacins from bioactive extracts of C. indica (Coccinoside A, B, and C) and M. balsamina (cucurbit-5, 7-dien-3ß-ol, cucurbita-5-en-3ß-ol-3-O-ß-d-glucopyranoside, and cucurbit-5-en-3ß-ol-3-O-ß-d-glucopyranosyl-(4’→1”)-O-ß-d-glucopyranoside) have been reported for the first time.The study concludes that the inclusion of C. indica and M. balsamina fruits in food can be useful for newly diagnosed diabetic patients or high risk group of population for glycemic control. Abbreviation used: C: indica (Coccinia indica), M: balsamina (Momordica balsamina), Kbr: Potassium bromide, FTIR: Fourier transform infrared spectroscopy, COSY: Corelated Spectroscopy, DEPT: Distortionless Enhancement by Polarization Transfer, DMSO: Dimethyl sulfoxide, TMS: tetramethylsilane, ESI-MS: Electrospray Ionization mass spectrometry, TLC: thin layer chromatography, STZ-NA: Streptozotocin-nicotinamide, CMC: carboxy methyl cellulose, BW: body weight, ANOVA: analysis of variance, AUC: area under curve

Cucurbitane-type triterpenoids from the aerial parts of Momordica charantia L.

Six new cucurbitane-type triterpenoids (1–6), together with two known analogues (7 and 8) were isolated from the aerial parts of Momordica charantia L. The structures of new compounds were identified as cucurbita-6,24-dien-3β,23-diol-19,5β-olide (1), (19R)-5β,19-epoxy-19-methoxycucurbita-6,24-dien-3β,23-diol (2), (19S)-5β,19-epoxy-19-methoxycucurbita-6,24-dien-3β,23-diol (3), (19R)-5β,19-epoxy-19-isopropoxycucurbita-6,24-dien-3β,23-diol (4), 3β,23-dihydroxy-5-methoxycucurbita-6,24-dien-19-al (5) and (19R)-7β,19-epoxy-19-methoxycucurbita-5,24-dien-3β,23-diol (6), by extensive MS, 1D and 2D NMR spectroscopic technologies. This is the first report of the isolation of tetracyclic triterpenoids possessing a 7β,19-epoxy system, viz., 6, from M. charantia L.

An Efficient Liquid-Phase Microextraction Method Combined with UHPLC-ELSD/MS for Analysis of Cucurbitane Triterpenoids in Bitter Melon Drinks

Momordica charantia L. of family Cucurbitaceae, also known as bitter melon, is a tropical and subtropical vine grown in Asia and Africa. Earlier studies showed that cucurbitane-type triterpenoids were the major active constituents responsible for the hypoglycemic effects exerted by M. charantia [1]. Liquid-phase microextraction is an efficient tool to extract and concentrate analytes of interest from complex matrices, such as plant, medicine, and bio-samples in recent years [2]. In the present work, a simple and effective vortex-assisted dispersive microextraction method is developed for extraction and concentration of cucurbitane triterpenoids (Momordicoside L, Momordicoside K, Momordicoside F2, and 3β,7β,25-trihydroxy cucurbita-5, (23E)-dien-19al) in bitter melon drinks prior to the determination by UPLC-ELSD/MS. Different solvents, volume of extract solvent, pH range, salt amount, and other variables influencing extraction efficiency were optimized. Recoveries and precision were tested with satisfactory results under the optimum conditions. Enrichment factors of 27 to 63-fold were obtained for four compounds. The apparent solvent/water partition coefficients of analytes were calculated within the range of 53 – 120. The proposed method can effectively enrich and quantitate cucurbitane triterpenoids from bitter melon drinks.

Triterpenoids from Ainsliaea henryi and their cytotoxic activities

Three new cucurbitane-type triterpenoids, including (23E)-cucurbita-3β-hydroxy-25-methoxy-5,23-diene (1), (23E)-cucurbita-3β-hydroxy-5,23,25-triene (2), and cucurbiata-3β-hydroxy-5,25-dien-24-one (3), have been isolated with four known triterpenoids (4-7) from the dried whole plants of Ainsliaea henryi. The chemical structures of compounds 1–3 were elucidated by 1D NMR (1H, 13C and DEPT), 2D NMR (COSY, HMBC, HSQC and NOESY) and HREIMS analyses. Among these compounds, compound 3 exhibited strong cytotoxicity against human cancer cell lines MGC 803 (IC50=8.33±0.94μM) and CCRF-CEM (IC50=4.34± 0.41μM), while compound 6 significantly inhibited the proliferation of the A549 and HCT 116 cell lines with IC50 values of 2.14±0.25 and 6.84±0.39μM, respectively.

Methyl jasmonate-induced accumulation of metabolites and transcriptional responses involved in triterpene biosynthesis in Siraitia grosvenorii fruit at different growing stages

The cucurbitane-type triterpenoid glycosides, mogrosides, are the main active components of &lt;em&gt;Siraitia grosvenorii&lt;/em&gt; fruit. Squalene and cucurbitadienol are among the intermediates of the biosynthetic pathway for the formation of cucurbitane-type triterpenoid backbones of mogrosides. It is recognized that the exogenous application of methyl jasmonate (MeJA) increases the accumulation of secondary metabolites in various plant species. Here, the effect of MeJA (50, 200, and 500 μM) on the accumulation of squalene and cucurbitadienol in the fruits of &lt;em&gt;S. grosvenorii&lt;/em&gt; at 10, 20, and 30 days after flowering (DAF) was tested for the first time. Since mogroside II E is the main cucurbitane-type triterpenoid present at this time, its concentration was also determined. The results show that MeJA can indeed promote squalene and cucurbitadienol accumulation, the application of 500 μM MeJA at 30 DAF being optimal. The concentration of squalene and cucurbitadienol increased up to 0.43 and 4.71 μg/g dry weight (DW), respectively, both of which were 1.2-fold greater than that of the control. The content of mogroside II E increased by 15% over the untreated group. We subsequently analyzed the expression of key genes involved in the mogroside biosynthetic pathway, including the 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene (&lt;em&gt;SgHMGR&lt;/em&gt;), squalene synthetase gene (&lt;em&gt;SgSQS&lt;/em&gt;), cucurbitadienol synthase gene (&lt;em&gt;SgCS&lt;/em&gt;), and cytochrome P450 (&lt;em&gt;SgCYP450&lt;/em&gt;) with quantitative real-time PCR. The results showed that transcriptional levels of these genes were upregulated following the treatment described above. Additionally, their responses in the presence of MeJA was related to the concentration and timing of MeJA treatment.

Di- and Triterpenoids from the Leaves of Casearia balansae and Neurite Outgrowth Promoting Effects of PC12 Cells.

A bioassay-guided phytochemical investigation of the leaves of Casearia balansae led to the isolation of six new cucurbitane-type triterpenoid derivatives (balanterpenes A-F, 1-6) and four new clerdoane-type diterpenoids (balanterpenes G-J, 7-10). The structures of 1-10 were established on the basis of extensive analysis of NMR spectroscopic data, X-ray crystallography, and experimental and calculated electronic circular dichroism spectra. Compound 1 features a ring-expanded triterpenoid skeleton with the C-19 methyl involved in the ring formation, compound 6 possesses a rare hexanortriterpenoid scaffold, and compounds 7-10 may be four new diterpenoid artifacts presumably formed during the extraction and purification processes. Compounds 3 and 7-10 showed promoting effects on neurite outgrowth of PC12 cells with EC50 values in the range 2.9-10.0 μM.

One new 19-nor cucurbitane-type triterpenoid from the stems of Momordica charantia

One new 19-nor cucurbitane-type triterpenoid (3β,9β,25-trihydroxy-7β-methoxy-19-nor-cucurbita-5,23(E)-diene) (1), together with other six known cucurbitane-type triterpenoids (2–7), were isolated from the stems of Momordica charantia L. The chemical structure of 1 was elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY and ROESY), MS experiments. Using MTT assay, compound 1 exhibited weak cytotoxicity against HL-60, A-549, and SK-BR-3 cell lines with the IC50 values at 27.3, 32.7 and 26.6 μM, respectively.

Two new cucurbitane-type triterpenoid saponins isolated from ethyl acetate extract of Citrullus colocynthis fruit

Two new cucurbitacins I (1 and 2), together with eight known compounds (3–10), were isolated from the ethyl acetate extract of the fruit of Citrullus colocynthis. Compounds 3, 5–9 were isolated from C. colocynthis for the first time. The structures of new compounds were determined primarily from IR, HR-MS, 1D-, and 2D-NMR analysis.

Cucurbitane-type triterpenoids from the stems and leaves of Momordica charantia

Six new cucurbitane-type triterpenoids, karavilagenin F (1), karavilosides XII and XIII (2, 3), momordicines VI, VII, and VIII (4, 5 and 6), along with four known ones, 5β,19-epoxy-25-methoxycucurbita-6,23-diene-3β,19-diol (7), 5β,19-epoxycucurbita-6, 23-diene-3β,19,25-triol (8), kuguacin R (9), and (19R,23E)-5β,19-epoxy-19-methoxycucurbita-6,23,25-trien-3β-ol (10), were isolated from the stems and leaves of Momordica charantia L. Their chemical structures were elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY, and ROESY), MS experiments, and CD spectrum. Compound 6 showed weak cytotoxicity against five human cancer cells lines with IC50 values of 14.3–20.5μmol/L.

Cucurbitane-type triterpenoids from the leaves of Momordica charantia

Phytochemical investigation of the ethanol extract from the leaves of Momordica charantia L. led to the isolation of two new (1, 2) and four known (3–6) cucurbitane-type triterpenoids. Their structures were elucidated on the basis of extensive analyses of spectroscopic data including IR, UV, MS, 1D, and 2D NMR. Also the absolute configurations of momordicines I (3) and II (4) were determined for the first time by application of the modified Mosher's method, acid hydrolysis, and GC analysis.

Cucurbitane-Type Triterpenoids from the Fruit Pulp of Momordica Charantia

Three new cucurbitane-type triterpenoids, 5beta,19-epoxy-23(R)-methoxycucurbita-6,24-dien-3beta-ol (1), 5beta,19-epoxy-23(S)-methoxycucurbita-6,24-dien-3beta-ol (2), and 3beta-hydroxy-23(R)-methoxycucurbita-6,24-dien-5beta,19-olide (3), were isolated from the fruit pulp of Momordica charantia. Their structures were established on the basis of extensive NMR (1H, 13C, COSY, HMQC, HMBC, and NOESY) and EI-MS studies. Compound 1 exhibited cytotoxic activity against the SK-Hep 1 cell line.