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1.
Mol Biol Rep ; 48(3): 2497-2505, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33837902

RESUMO

Globally, breast cancer is a serious concern that exhibits a persistent rise in its incidence and related mortality even after significant advancement in the field of cancer research. To find an alternative cure for the disease from natural resources we selected Bacopa monniera, a perennial ethnomedicinal plant popularly used for boosting memory and mental health. We isolated four different types of dammarane saponins, namely bacopasaponins C-F (1-4) from the plant and evaluated their toxic effects on two different types of human breast cancer cell lines-a hormone-responsive MCF7 and a triple-negative MDA-MB-231. Interestingly, MTT assay revealed a dose-dependent toxic effect of all four types of bacopasaponins on both of these cell lines, 4 being the most effective with 48 h-inhibitory concentration (IC50) of 32.44 and 30 µM in MCF7 and MDA-MB-231 respectively. Further, 4 caused significant alterations in normal cytomorphology and induction of apoptosis in both of these cell lines after 48 h of treatment. No caspase-8 activity was detected in these cell lines when exposed to 4 for 2, 24, and 48 h; instead, Western blotting analysis confirmed involvement of either caspase-9 (MCF7) or both caspase-9 and caspase-3 (MDA-MB-231) in the process of apoptosis indicating the occurrence of intrinsic mode. Additionally, at comparable effective doses to cancer, bacopasaponins showed much less toxicity in normal human peripheral blood lymphocytes (≥ 85% cell survival). Overall, the findings project bacopasaponin F, a natural constituent of Bacopa monniera, as an efficient and safer alternative for breast cancer therapeutics.


Assuntos
Neoplasias da Mama/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Saponinas/química , Triterpenos/química
2.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916654

RESUMO

A novel botanical dietary supplement, formulated as a chewable tablet containing a defined mixture of Souroubea spp. vine and Platanus spp. Bark, was tested as a canine anxiolytic for thunderstorm noise-induced stress (noise aversion). The tablet contained five highly stable triterpenes and delivered 10 mg of the active ingredient betulinic acid (BA) for an intended 1 mg/kg dose in a 10 kg dog. BA in tablets was stable for 30 months in storage at 23 °C. Efficacy of the tablets in reducing anxiety in dogs was assessed in a blinded, placebo-controlled study by recording changes in blood cortisol levels and measures of behavioral activity in response to recorded intermittent thunder. Sixty beagles were assigned into groups receiving: placebo, 0.5×, 1×, 2×, and 4× dose, or the positive control (diazepam), for five days. Reduction in anxiety measures was partially dose-dependent and the 1× dose was effective in reducing inactivity time (p = 0.0111) or increased activity time (p = 0.0299) compared with placebo, indicating a decrease in anxiety response. Cortisol measures also showed a dose-dependent reduction in cortisol in dogs treated with the test tablet.


Assuntos
Ansiedade/terapia , Suplementos Nutricionais , Ericales/química , Medo/efeitos dos fármacos , Magnoliopsida/química , Triterpenos/farmacologia , Animais , Ansiedade/sangue , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Hidrocortisona/sangue , Análise dos Mínimos Quadrados , Comprimidos , Triterpenos/química
3.
Molecules ; 26(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809511

RESUMO

Triterpenoids have regained much attention as promising multi-targeting bioactive agents of natural origin in the treatment of numerous disorders. Due to the high potential for phytopharmaceutical development, accurate qualitative and quantitative analysis of triterpenoids for screening and quality control is required. Vaccinium vitis-idaea L. (lingonberry) raw materials have aroused interest as a rich source of triterpenoids. However, currently, no validated, rapid, and easy-to-perform quantification method is available for the routine control of these compounds in lingonberries. This research aimed at developing and validating HPLC-PDA methods for the determination and screening of triterpenoids in extracts of lingonberry leaves, fruits, and flowers. The developed methods were deemed satisfactory by validation, which revealed acceptable analytical specificity, linearity (r2 > 0.9999), precision (RSD < 2%), trueness (94.70-105.81%), and sensitivity (LOD: 0.08-0.65 µg/mL). The real sample analysis demonstrated established methods applicability for quantification of 13 triterpenoids in lingonberries and emphasized differences between raw materials. Lingonberry fruits were distinguished by the richness of ursolic acid; lingonberry flowers by similar profile to fruits, but low content of neutral triterpenoids; whereas lingonberry leaves by the particularly high level of α-amyrin. Thus, the proposed methods proved to be reliable and applicable for quantification and routine analysis of triterpenoids in lingonberry samples.


Assuntos
Triterpenos/química , Vaccinium vitis-Idaea/química , Cromatografia Líquida de Alta Pressão/métodos , Flores/química , Frutas/química , Triterpenos Pentacíclicos/química , Extratos Vegetais/química , Folhas de Planta/química , Controle de Qualidade , Vaccinium myrtillus/química
4.
Molecules ; 26(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809760

RESUMO

Investigation of the methanol extract of the poroid fungus Fuscoporia torulosa resulted in the isolation of a novel triterpene, fuscoporic acid (1), together with inoscavin A and its previously undescribed Z isomer (2 and 3), 3,4-dihydroxy-benzaldehide (4), osmundacetone (5), senexdiolic acid (6), natalic acid (7), and ergosta-7,22-diene-3-one (8). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analyses, as well as molecular modeling studies. Compounds 1, 6-8 were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines. Compound 8 was effective against Colo 205 (IC50 11.65 ± 1.67 µM), Colo 320 (IC50 8.43 ± 1.1 µM) and MRC-5 (IC50 7.92 ± 1.42 µM) cell lines. Potentially synergistic relationship was investigated between 8 and doxorubicin, which revealed a synergism between the examined compounds with a combination index (CI) at the 50% growth inhibition dose (ED50) of 0.521 ± 0.15. Several compounds (1 and 6-8) were tested for P-glycoprotein modulatory effect in Colo 320 resistant cancer cells, but none of the compounds proved to be effective in this assay. Fungal metabolites 2-5 were evaluated for their antioxidant activity using the oxygen radical absorbance capacity (ORAC) and DPPH assays. Compounds 4 and 5 were found to have a considerable antioxidant effect with EC50 0.25 ± 0.01 (DPPH) and 12.20 ± 0.92 mmol TE/g (ORAC). The current article provides valuable information on both the chemical and pharmacological profiles of Fuscoporia torulosa, paving the way for future studies with this species.


Assuntos
Basidiomycota/química , Fenóis/química , Fenóis/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/fisiologia , Linhagem Celular Tumoral , Humanos , Metanol/química
5.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808219

RESUMO

Biomimetic (non-cell based in vitro) and computational (in silico) studies are commonly used as screening tests in laboratory practice in the first stages of an experiment on biologically active compounds (potential drugs) and constitute an important step in the research on the drug design process. The main aim of this study was to evaluate the ability of triterpenoid saponins of plant origin to cross the blood-brain barrier (BBB) using both computational methods, including QSAR methodology, and biomimetic chromatographic methods, i.e., High Performance Liquid Chromatography (HPLC) with Immobilized Artificial Membrane (IAM) and cholesterol (CHOL) stationary phases, as well as Bio-partitioning Micellar Chromatography (BMC). The tested compounds were as follows: arjunic acid (Terminalia arjuna), akebia saponin D (Akebia quinata), bacoside A (Bacopa monnieri) and platycodin D (Platycodon grandiflorum). The pharmacokinetic BBB parameters calculated in silico show that three of the four substances, i.e., arjunic acid, akebia saponin D, and bacoside A exhibit similar values of brain/plasma equilibration rate expressed as logPSFubrain (the average logPSFubrain: -5.03), whereas the logPSFubrain value for platycodin D is -9.0. Platycodin D also shows the highest value of the unbound fraction in the brain obtained using the examined compounds (0.98). In these studies, it was found out for the first time that the logarithm of the analyte-micelle association constant (logKMA) calculated based on Foley's equation can describe the passage of substances through the BBB. The most similar logBB values were obtained for hydrophilic platycodin D, applying both biomimetic and computational methods. All of the obtained logBB values and physicochemical parameters of the molecule indicate that platycodin D does not cross the BBB (the average logBB: -1.681), even though the in silico estimated value of the fraction unbound in plasma is relatively high (0.52). As far as it is known, this is the first paper that shows the applicability of biomimetic chromatographic methods in predicting the penetration of triterpenoid saponins through the BBB.


Assuntos
Biomimética/métodos , Barreira Hematoencefálica/efeitos dos fármacos , Saponinas/química , Saponinas/farmacocinética , Colesterol/química , Cromatografia Líquida de Alta Pressão , Cromatografia Capilar Eletrocinética Micelar , Simulação por Computador , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Triterpenos/química , Triterpenos/farmacocinética
6.
Int J Mol Sci ; 22(7)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808384

RESUMO

A molecular docking approach was employed to evaluate the binding affinity of six triterpenes, namely epifriedelanol, friedelin, α-amyrin, α-amyrin acetate, ß-amyrin acetate, and bauerenyl acetate, towards the cannabinoid type 1 receptor (CB1). Molecular docking studies showed that friedelin, α-amyrin, and epifriedelanol had the strongest binding affinity towards CB1. Molecular dynamics simulation studies revealed that friedelin and α-amyrin engaged in stable non-bonding interactions by binding to a pocket close to the active site on the surface of the CB1 target protein. The studied triterpenes showed a good capacity to penetrate the blood-brain barrier. These results help to provide some evidence to justify, at least in part, the previously reported antinociceptive and sedative properties of Vernonia patula.


Assuntos
Receptores de Canabinoides/química , Vernonia/química , Vernonia/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Triterpenos Pentacíclicos/química , Receptores de Canabinoides/metabolismo , Receptores de Canabinoides/fisiologia , Triterpenos/química
7.
Molecules ; 26(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919839

RESUMO

Pentacyclic triterpenes are important representatives of natural products that exhibit a wide variety of biological activities. These activities suggest that these compounds may represent potential medicines for the treatment of cancer and viral, bacterial, or protozoal infections. Naturally occurring triterpenes usually have several drawbacks, such as limited activity and insufficient solubility and bioavailability; therefore, they need to be modified to obtain compounds suitable for drug development. Modifications can be achieved either by methods of standard organic synthesis or with the use of biocatalysts, such as enzymes or enzyme systems within living organisms. In most cases, these modifications result in the preparation of esters, amides, saponins, or sugar conjugates. Notably, while standard organic synthesis has been heavily used and developed, the use of the latter methodology has been rather limited, but it appears that biocatalysis has recently sparked considerably wider interest within the scientific community. Among triterpenes, derivatives of lupane play important roles. This review therefore summarizes the natural occurrence and sources of lupane triterpenoids, their biosynthesis, and semisynthetic methods that may be used for the production of betulinic acid from abundant and inexpensive betulin. Most importantly, this article compares chemical transformations of lupane triterpenoids with analogous reactions performed by biocatalysts and highlights a large space for the future development of biocatalysis in this field. The results of this study may serve as a summary of the current state of research and demonstrate the potential of the method in future applications.


Assuntos
Biocatálise , Triterpenos/química , Descoberta de Drogas , Hidrólise , Oxirredução , Triterpenos/síntese química
8.
Molecules ; 26(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801575

RESUMO

Momordica balsamina leaf extracts originating from three different geographical locations were analyzed using reversed-phase liquid chromatography (RP-LC) coupled to travelling wave ion mobility (TWIMS) and high-resolution mass spectrometry (HRMS) in conjunction with chemometric analysis to differentiate between potential chemotypes. Furthermore, the cytotoxicity of the three individual chemotypes was evaluated using HT-29 colon cancer cells. A total of 11 molecular species including three flavonol glycosides, five cucurbitane-type triterpenoid aglycones and three glycosidic cucurbitane-type triterpenoids were identified. The cucurbitane-type triterpenoid aglycones were detected in the positive ionization mode following dehydration [M + H - H2O]+ of the parent compound, whereas the cucurbitane-type triterpenoid glycosides were primarily identified following adduct formation with ammonia [M + NH4]+. The principle component analysis (PCA) loadings plot and a variable influence on projection (VIP) analysis revealed that the isomeric pair balsaminol E and/or karavilagen E was the key molecular species contributing to the distinction between geographical samples. Ultimately, based on statistical analysis, it is hypothesized that balsaminol E and/or karavilagen E are likely responsible for the cytotoxic effects in HT-29 cells.


Assuntos
Antineoplásicos Fitogênicos/química , Flavonóis/química , Glicosídeos/química , Momordica/química , Triterpenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromatografia de Fase Reversa , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Células HT29 , Humanos , Concentração Inibidora 50 , Espectrometria de Massas/métodos , Extratos Vegetais/química , Folhas de Planta/química , Análise de Componente Principal , Relação Estrutura-Atividade , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
9.
Molecules ; 26(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924283

RESUMO

Radix Astragali is referred to as a variety of food-medicine herb, and it is commonly applied as Traditional Chinese Medicine (TCM). However, it is extremely difficult to extract its bio-active compounds (astragaloside IV) and apply it in food processing efficiently, which restricts its practical applications. In this study, the conditions required for the extraction of astragaloside IV were optimized by following the response surface methodology. More specifically, ammonia with a concentration of 24% was used as an extracting solvent, the solid-liquid ratio was 1:10 (w:v); the Radix Astragali was soaked at 25 °C for 120 min in advance and then stirred at 25 °C for 52 min (150 rpm) to extract astragaloside IV. This method promoted the transformation of other astragalosides into astragaloside IV and replaced the traditional approach for extraction, the solvent reflux extraction method. The yield of astragaloside IV reached the range of 2.621 ± 0.019 mg/g. In addition, the stability of astragaloside IV was evaluated by detecting its retention rate during sterilization and 60-day storage. As suggested by the results, the astragaloside IV in acidic, low-acidic, and neutral solutions was maintained above 90% after sterilization (95 °C and 60 min) but below 60% in an alkaline solution. High temperature and short-term sterilization approach is more appropriate for astragaloside IV in an alkaline solution. It was also found out that the astragaloside IV obtained using our method was maintained over 90% when stored at room temperature (25 °C), and there was no significant difference observed to low temperature (4 °C) in solutions regardless of acidity.


Assuntos
Astrágalo (Planta)/química , Medicina Tradicional Chinesa , Plantas Medicinais/química , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Humanos , Raízes de Plantas/química , Estabilidade Proteica/efeitos dos fármacos , Saponinas/química , Esterilização , Propriedades de Superfície , Triterpenos/química
10.
Molecules ; 26(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919344

RESUMO

Cytotoxicity and apoptosis-inducing properties of compounds isolated from Garcinia subelliptica leaves were investigated. The hexane-soluble portion of MeOH extracts of G. subelliptica leaves that showed cytotoxic activity was separated to yield seven compounds 1-7. Chemical structure analysis using NMR spectroscopy and mass spectrometry confirmed that compound 1 was canophyllol, and compounds 2-7 were garcinielliptones N, O, J, G, F, and garcinielliptin oxide, respectively. Among them, garcinielliptone G (5) showed growth inhibition by causing apoptosis in THP-1 and Jurkat cells derived from human acute monocytic leukemia and T lymphocyte cells, respectively. Apoptosis induced by garcinielliptone G (5) was demonstrated by the detection of early apoptotic cells with fluorescein-labeled Annexin V and increases in cleaved caspase-3 and cleaved PARP protein levels. However, the addition of caspase inhibitor Z-VAD-FMK did not affect growth arrest or apoptosis induction. These results suggest that garcinielliptone G (5) can induce both caspase-3 activation and caspase-independent apoptosis. Therefore, garcinielliptone G (5) may be a potential candidate for acute leukemia treatment.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Garcinia/química , Triterpenos/química , Triterpenos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Leucemia , Células THP-1
11.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920841

RESUMO

Obesity has a strong relationship to insulin resistance and diabetes mellitus, a chronic metabolic disease that alters many physiological functions. Naturally derived drugs have aroused great interest in treating obesity, and triterpenoids are natural compounds with multiple biological activities and antidiabetic mechanisms. Here, we evaluated the bioactivity of ursolic acid lactone (UAL), a lesser-known triterpenoid, obtained from Eucalyptus tereticornis. We used different cell lines to show for the first time that this molecule exhibits anti-inflammatory properties in a macrophage model, increases glucose uptake in insulin-resistant muscle cells, and reduces triglyceride content in hepatocytes and adipocytes. In 3T3-L1 adipocytes, UAL inhibited the expression of genes involved in adipogenesis and lipogenesis, enhanced the expression of genes involved in fat oxidation, and increased AMP-activated protein kinase phosphorylation. The range of biological activities demonstrated in vitro indicates that UAL is a promising molecule for fighting diabetes.


Assuntos
Eucalyptus/química , Lactonas/química , Lactonas/farmacologia , Triterpenos/química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Macrófagos , Camundongos , Células Musculares/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo , Triterpenos/farmacologia
12.
Molecules ; 26(9)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922678

RESUMO

Extracts of the fungus Inonotus obliquus exhibit cytotoxic properties against different cancers; hence, this fungal species has been extensively studied. This study aimed to extract total triterpenoids from Inonotus obliquus using ionic liquids (ILs) and separate potential lactate dehydrogenase (LDH) inhibitors via ultrafiltration (UF)-high-speed countercurrent chromatography (HSCCC). Total triterpenoids from Inonotus obliquus were extracted by performing a single-factor experiment and employing a central composite design via ultrasonic-assisted extraction (UAE) and heat-assisted extraction (HAE). The extract was composed of 1-butyl-3-methylimidazolium bromide as the IL and methanol as the dispersant. Ultrafiltration-liquid chromatography (UF-LC) was used to rapidly scan the LDH inhibitors and betulin and lanosterol were identified as potential inhibitors. To obtain these target compounds, betulin and lanosterol with the purities of 95.9% and 97.8% were isolated from HSCCC within 120 min. Their structures were identified using several techniques, among which IL-HAE was fast and effective. This study reports the extraction of triterpenoids from Inonotus obliquus by IL for the first time. Collectively, the findings demonstrate that UF-LC is an effective tool for screening potential LDH inhibitors from crude extracts of I. obliquus and may help to identify bioactive substances against myocardial infarction, whereas high-purity compounds can be separated via UF-HSCCC.


Assuntos
Distribuição Contracorrente/métodos , Líquidos Iônicos/química , Triterpenos/química , Ultrafiltração/métodos , Cromatografia Líquida , L-Lactato Desidrogenase/metabolismo
13.
Int J Nanomedicine ; 16: 1775-1787, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692622

RESUMO

Purpose: To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo. Methods: UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models. Results: Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy. Conclusion: Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Receptores de Folato com Âncoras de GPI/metabolismo , Metotrexato/farmacologia , Nanopartículas/química , Triterpenos/farmacologia , Animais , Antineoplásicos/administração & dosagem , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Feminino , Ácido Fólico/química , Humanos , Células MCF-7 , Metotrexato/administração & dosagem , Metotrexato/química , Camundongos Nus , Nanopartículas/ultraestrutura , Ratos Wistar , Triterpenos/administração & dosagem , Triterpenos/química
14.
Molecules ; 26(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668176

RESUMO

Colorectal cancer is a common cancer worldwide and reduced expression of the DNA repair endonuclease XPF (xeroderma pigmentosum complementation group F) is associated with colorectal cancer. Bacopa monnieri extracts were previously found to exhibit chemical-genetic synthetic lethal effects in a Saccharomyces cerevisiae model of colorectal cancer lacking Rad1p, a structural and functional homologue of human XPF. However, the mechanisms for B. monnieri extracts to limit proliferation and promote an apoptosis-like event in RAD1 deleted yeast was not elucidated. Our current analysis has revealed that B. monnieri extracts have the capacity to promote mutations in rad1∆ cells. In addition, the effects of B. monnieri extracts on rad1∆ yeast is linked to disruption of the vacuole, similar to the mammalian lysosome. The absence of RAD1 in yeast sensitizes cells to the effects of vacuole disruption and the release of proteases. The combined effect of increased DNA mutations and release of vacuolar contents appears to induce an apoptosis-like event that is dependent on the meta-caspase Yca1p. The toxicity of B. monnieri extracts is linked to sterol content, suggesting saponins may be involved in limiting the proliferation of yeast cells. Analysis of major constituents from B. monnieri identified a chemical-genetic interaction between bacopasaponin C and rad1∆ yeast. Bacopasaponin C may have potential as a drug candidate or serve as a model for the development of analogs for the treatment of colorectal cancer.


Assuntos
Bacopa/química , Enzimas Reparadoras do DNA/metabolismo , Endonucleases/metabolismo , Glicosídeos/farmacologia , Extratos Vegetais/farmacologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Triterpenos/farmacologia , Vacúolos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/genética , Endonucleases/deficiência , Endonucleases/genética , Glicosídeos/química , Extratos Vegetais/química , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Triterpenos/química , Vacúolos/metabolismo
15.
Molecules ; 26(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669312

RESUMO

Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-ß-d-allopyranosyl-5ß,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-ß-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2-6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0-76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.


Assuntos
Anti-Inflamatórios/farmacologia , Simulação por Computador , Frutas/química , Glicosídeos/química , Glicosídeos/farmacologia , Hipoglicemiantes/farmacologia , Momordica charantia/química , Triterpenos/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Bioensaio , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Glicosídeos/isolamento & purificação , Hipoglicemiantes/química , Ligantes , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triterpenos/isolamento & purificação , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
16.
Molecules ; 26(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670791

RESUMO

Betulinic acid (BA, 3ß-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/farmacologia , Antiprotozoários/química , Modelos Moleculares , Triterpenos Pentacíclicos/química , Triterpenos/química
17.
Molecules ; 26(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525521

RESUMO

In continuation of our studies on a Vietnamese collection of a Stelletta sp., sponge we have isolated two new isomalabaricane triterpenoids, stellettins Q and R (1 and 2), and four new isomalabaricane-derived nor-terpenoids, stellettins S-V 3-6, along with previously known globostelletin N. Among them, compound 3 contains an acetylenic fragment, unprecedented in the isomalabaricane family and extremely rare in other marine sponge terpenoids. The structures and absolute configurations of all new compounds were established by extensive NMR, MS, and ECD analyses together with quantum-chemical modeling. Additionally, according to obtained new data we report the correction in stereochemistry of two asymmetric centers in the structures of two known isomalabaricanes, 15R,23S for globostelletin M and 15S,23R for globostelletin N.


Assuntos
Poríferos/química , Poríferos/metabolismo , Terpenos/química , Triterpenos/química , Alcinos/química , Animais
18.
Molecules ; 26(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567740

RESUMO

Influenza outbreaks pose a serious threat to human health. Hemagglutinin (HA) is an important target for influenza virus entry inhibitors. In this study, we synthesized four pentacyclic triterpene conjugates with a sialylglycopeptide scaffold through the Cu(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) and prepared affinity assays of these conjugates with two HAs, namely H1N1 (A/WSN/1933) and H5N1 (A/Hong Kong/483/97), respectively. With a dissociation constant (KD) of 6.89 µM, SCT-Asn-betulinic acid exhibited the strongest affinity with the H1N1 protein. Furthermore, with a KD value of 9.10 µM, SCT-Asn-oleanolic acid exhibited the strongest affinity with the H5N1 protein. The conjugates considerably enhanced antiviral activity, which indicates that pentacyclic triterpenes can be used as a ligand to improve the anti-influenza ability of the sialylglycopeptide molecule by acting on the HA protein.


Assuntos
Glicopeptídeos/química , Hemaglutininas/metabolismo , Triterpenos/química , Triterpenos/metabolismo , Técnicas de Química Sintética , Ressonância de Plasmônio de Superfície , Triterpenos/síntese química
19.
Molecules ; 26(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572631

RESUMO

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 µM, and, for 7b, they were 0.76 and 0.8 µM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Fosfatos/química , Triterpenos/química , Triterpenos/farmacologia , Linhagem Celular Tumoral , Humanos , Conformação Molecular
20.
Molecules ; 26(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572779

RESUMO

Plants have been used for thousands of years for various purposes because they have a wide variety of activities with biological significance. Mexican oregano is an aromatic plant of great importance to Mexico and north of Jalisco state as a spice with important economic value. Chromatographic identification and quantification of phenolic compounds and evaluation of their antioxidant activity were important tools to obtain a better characterization of this spice. Phytochemical analysis indicated the presence of flavonoids, triterpenes, saponins, quinones and tannins, the latter at high concentrations. Through chromatographic assays of Mexican oregano extracts, 62 compounds were identified, the major ones being quantified as: taxifolin, apigenin 7-O-glucoside, phlorizin, eriodictyol, quercetin, naringenin, hispidulin, pinocembrin, galangin and genkwanin (compound for the first time reported for this species). The results can be useful as a precedent to establish the bases of new quality characterization parameters and they have also suggested that Mexican oregano contains a wide variety of compounds with untapped importance for the development of new high value-added products.


Assuntos
Antioxidantes/química , Origanum/química , Fenóis/química , Flavonoides/química , Humanos , Fenóis/classificação , Fenóis/isolamento & purificação , Extratos Vegetais/química , Quinonas/química , Saponinas/química , Taninos/química , Triterpenos/química
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