RESUMEN

The goal of preparative chromatography is to isolate suitable amounts of compound(s) at the required purity in the most cost-effective way. This study analyses the power of High-performance thin-layer chromatography (HPTLC) guided preparative flash chromatography to separate and isolate bioactive compounds from an olive flower extract for their further characterisation via spectroscopy. The structure and purity of isolated bioactive compounds were assessed using Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Flash chromatography of the olive flower extract successfully isolated pure oleanolic and maslinic acids. Moreover, the flash chromatography of the extract allowed isolation and phytochemical analysis of the most lipophilic fraction of the extract, which was found to contain n-eicosane and n-(Z)-eicos-5-ene, that has not been isolated previously with preparative TLC.

Asunto(s)

Flores , Espectroscopía de Resonancia Magnética , Olea , Extractos Vegetales , Flores/química , Cromatografía en Capa Delgada/métodos , Olea/química , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Espectroscopía Infrarroja por Transformada de Fourier , Triterpenos/análisis , Triterpenos/aislamiento & purificación , Triterpenos/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análisis , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos

RESUMEN

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.

Asunto(s)

Apoptosis , Neoplasias de la Mama , Quitosano , Heparina , Ácido Oleanólico , Quitosano/química , Quitosano/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Femenino , Ratones , Apoptosis/efectos de los fármacos , Heparina/química , Heparina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Portadores de Fármacos/química , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Basidiomycetes with a wide variety of skeletons of secondary metabolites can be expected to be the source of new interesting biological compounds. During our research on basidiomycetes, two new C-29 oxygenated oleanane-type triterpenes (1 and 2) and torulosacid (3), a muurolene type sesquiterpenoid with a five-membered ether ring along with nine known compounds (4-12), were isolated from the MeOH extract of the fruiting bodies of Fuscoporia torulosa. The structures of 1-3 were determined by NMR and HREIMS analysis. Further studies on the stereochemistry of 3 were conducted using X-ray crystallographic analysis and comparison of experimental and calculated ECD spectra. In the antimicrobial assay of isolates, 1, 7, and 9 showed growth inhibitory activity against methicillin-resistant Staphylococcus aureus and other gram-positive strains. Isolation of oleanane type triterpenes from fungi including basidiomycetes, is a unique report that could lead to further isolation of new compounds and the discovery of unique biosynthetic enzymes.

Asunto(s)

Cuerpos Fructíferos de los Hongos , Pruebas de Sensibilidad Microbiana , Sesquiterpenos , Cuerpos Fructíferos de los Hongos/química , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Estructura Molecular , Basidiomycota/química , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/farmacología , Triterpenos/química , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Cristalografía por Rayos X , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos

RESUMEN

Triterpene acids are a class of pentacyclic natural carboxylic compounds endowed with a variety of biological activities including antitumor, antimicrobial, and hepatoprotective effects. In this work, several oleanolic acid derivatives were synthesized by structurally modifying them on the C-3 position. All synthesized derivatives were evaluated for possible antibacterial and antiviral activity, and among all the epimers, 6 and 7 demonstrated the best biological activities. Zone-of-inhibition analyses were conducted against two strains, E. coli as a Gram-negative and S. aureus as a Gram-positive model. Subsequently, experiments were performed using the microdilution method to determine the minimum inhibitory concentration (MIC). The results showed that only the derivative with reduced hydrogen bonding ability on ring A possesses remarkable activity toward E. coli. The conversion from acid to methyl ester implies a loss of activity, probably due to a reduced affinity with the bacterial membrane. Before the antiviral activity, the cytotoxicity of triterpenes was evaluated through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Samples 6 and 7 showed less than 50% cytotoxicity at 0.625 and 1 mg/mL, respectively. The antiviral activity against SARS-CoV-2 and PV-1 did not indicate that triterpene acids had any inhibitory capacity in the sub-toxic concentration range.

Asunto(s)

Antibacterianos , Antivirales , Escherichia coli , Pruebas de Sensibilidad Microbiana , Ácido Oleanólico , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Humanos , Staphylococcus aureus/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Animales , Relación Estructura-Actividad

RESUMEN

Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.

Asunto(s)

Ácido Oleanólico , Ratones , Animales , Células RAW 264.7 , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análogos & derivados , Estructura Molecular , Relación Estructura-Actividad , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/metabolismo

RESUMEN

The effective treatment of acute lung injury (ALI) remains a significant challenge. Patients with ALI demonstrate an abundance of proinflammatory mediators in both bronchoalveolar lavage fluid (BALF) and circulating plasma. Bardoxolone methyl (BM) is a semi-synthetic triterpenoid derived from oleanolic acid, a natural product known for its ability to inhibit proinflammatory signaling. GSDMD is a signaling protein involved in pyroptosis, a form of programmed cell death. It has been reported that its upstream proteins play a role in the pathogenesis of ALI. However, there is currently no research examining whether the effect of BM on the occurrence and development of ALI is associated with changes in GSDMD protein. In this study, we prepared nanostructured lipid carriers loaded with BM and conjugated with anti-PECAM-1 antibody (PECAM@BM NLCs). PECAM@BM NLCs were designed to specifically bind to pulmonary vascular endothelial cells that highly express the PECAM-1 receptors. We also aimed to investigate the protective effects of PECAM@BM NLCs on ALI and elucidate the underlying molecular mechanisms. The results demonstrated that PECAM@BM NLCs accumulated in the lung tissues and significantly alleviated the inflammatory injury of ALI. This was evidenced by the changes in the lung wet/dry ratio, the total protein concentration, proinflammatory cytokines in BALF, and the histopathological progress. Additionally, we elucidated that PECAM@BM NLCs had the ability to inhibit the assembly of NLRP3 inflammasome and pro-caspase-1 complex, thereby suppressing the induction of pyroptosis. This mechanism resulted in the inhibition of N-terminal GSDMD expression and effectively prevented the progression of ALI.

Asunto(s)

Lesión Pulmonar Aguda , Pulmón , Nanoestructuras , Ácido Oleanólico , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/administración & dosificación , Ácido Oleanólico/química , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Nanoestructuras/química , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Portadores de Fármacos/química , Masculino , Ratones , Neumonía/tratamiento farmacológico , Neumonía/patología , Neumonía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones Endogámicos C57BL , Lípidos/química , Anticuerpos/farmacología , Líquido del Lavado Bronquioalveolar/química , Humanos , Sistemas de Liberación de Medicamentos/métodos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos

RESUMEN

As an oleanolic acid derivative, CDDO-Me lacks selectivity for tumors. Based on the high reactive oxygen species (ROS) level in cancer cells, compound 4 was selected from 17 new CDDO arylboronate ester derivatives. A preliminary study revealed that 4 displayed the highest selectivity for cancer cells. Furthermore, 4 could be transformed to 4H by ROS to increase its covalent binding ability and antiproliferation effect (IC50 of 2.11 vs 0.37 µM) in BGC-823 cells. Interestingly, 4 increased ROS levels to induce apoptosis in BGC-823 cells. Moreover, the LD50 of 4 (91.2 mg/kg) was much greater than that of CDDO-Me (61.7 mg/kg) in ICR mice. A pharmacokinetic study indicated that 4 could be transformed to 4H in vivo. In addition, 4 exhibited a greater tumor inhibition rate (86.2%) than CDDO-Me (51.7%). Overall, the design of 4 provided an effective modification strategy for CDDO to increase the selectivity for cancer cells.

Asunto(s)

Antineoplásicos , Apoptosis , Proliferación Celular , Ratones Endogámicos ICR , Ácido Oleanólico , Animales , Humanos , Masculino , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Ácidos Borónicos/química , Ácidos Borónicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ésteres/química , Ésteres/farmacología , Ésteres/síntesis química , Estructura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/síntesis química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Formamidas/química , Formamidas/farmacología , Etilaminas/química , Etilaminas/farmacología

RESUMEN

Saikosaponins (SS), which are major bioactive compounds in Radix Bupleuri, have long been used clinically for multicomponent, multitarget, and multipathway therapeutic strategies. Programmed cell death (PCD) induction is among the multiple mechanisms of SS and mediates the anticancer efficacy of this drug family. Although SS show promise for anticancer therapy, the available data to explain how SS mediate their key anticancer effects through PCD (apoptosis, autophagy, ferroptosis, and pyroptosis) remain limited and piecemeal. This review offers an extensive analysis of the key pathways and mechanisms involved in PCD and explores the importance of SS in cancer. We believe that high-quality clinical trials and a deeper understanding of the pharmacological targets involved in the signalling cascades that govern tumour initiation and progression are needed to facilitate the development of innovative SS-based treatments. Elucidating the specific anticancer pathways activated by SS and further clarifying how comprehensive therapies lead to cross-link among the different types of cell death will inspire the clinical translation of SS as cancer treatments.

Asunto(s)

Apoptosis , Neoplasias , Ácido Oleanólico , Saponinas , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Humanos , Saponinas/farmacología , Saponinas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacos

RESUMEN

Plants from the Amaranthaceae family are a source of oleanolic acid (OA)-type saponins with cytotoxic activity. Two known OA-type saponins, calenduloside E and chikusetsusaponin IVa, were isolated from the roots of Chenopodium strictum Roth. Their structures were confirmed using MS and NMR techniques. This constitutes the inaugural report of the saponins in Ch. strictum. Both the isolated saponins and structurally similar compounds, momordin Ic and OA, were compared for their cytotoxicity against various cancer and normal cell lines (including skin, breast, thyroid, gastrointestinal, and prostate panels). Their effects were dose- and time-dependent, varying with the specific cell line and compound structure. A chemometric approach demonstrated the effects of the compounds on the cell lines. The study discusses the structure-activity observations. The key structural elements for potent cytotoxic activity included the free carboxyl group 28COOH in the sapogenin structure (OA) and the presence of a sugar moiety. The monodesmosides with glucuronic acid (GlcA) at the C3 position of OA were generally more cytotoxic than bidesmosides or OA alone. The addition of xylose in the sugar chain modified the activity towards the cancer cells depending on the specific cell line. OA-type saponins with GlcA (particularly calenduloside E and momordin Ic) represent a promising avenue for further investigation as potential anticancer agents.

Asunto(s)

Antineoplásicos Fitogénicos , Ácido Oleanólico , Saponinas , Humanos , Saponinas/farmacología , Saponinas/química , Saponinas/aislamiento & purificación , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Línea Celular Tumoral , Relación Estructura-Actividad , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Amaranthaceae/química , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ensayos de Selección de Medicamentos Antitumorales , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos

RESUMEN

The presented work aimed to explore the potential of oleanolic acid dimers (OADs): their cytostatic and antioxidant activities, molecular docking, pharmacokinetics, and ADMETox profile. The cytostatic properties of oleanolic acid (1) and its 14 synthesised dimers (2a-2n) were evaluated against 10 tumour types and expressed as IC50 values. Molecular docking was performed with the CB-Dock2 server. Antioxidant properties were evaluated with the CUPRAC method. ADMETox properties were evaluated with the ADMETlab Manual (2.0) database. The results indicate that the obtained OADs can be effective cytostatic agents, for which the IC50 not exceeded 10.00 for many tested cancer cell lines. All OADs were much more active against all cell lines than the mother compound (1). All dimers can inhibit the interaction between the 1MP8 protein and cellular proteins with the best results for compounds 2f and 2g with unsaturated bonds within the linker. An additional advantage of the tested OADs was a high level of antioxidant activity, with Trolox equivalent for OADs 2c, 2d, 2g-2j, 2l, and 2m of approximately 0.04 mg/mL, and beneficial pharmacokinetics and ADMETox properties. The differences in the DPPH and CUPRAC assay results obtained for OADs may indicate that these compounds may be effective antioxidants against different radicals.

Asunto(s)

Antioxidantes , Simulación del Acoplamiento Molecular , Ácido Oleanólico , Antioxidantes/química , Antioxidantes/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Humanos , Línea Celular Tumoral , Dimerización , Antineoplásicos/farmacología , Antineoplásicos/química , Estructura Molecular

RESUMEN

The rapid emergence of antibiotic resistance and the scarcity of novel antibacterial agents have necessitated an urgent pursuit for the discovery and development of novel antibacterial agents against multidrug-resistant bacteria. This study involved the design and synthesis of series of novel indole-benzosulfonamide oleanolic acid (OA) derivatives, in which the indole and benzosulfonamide pharmacophores were introduced into the OA skeleton semisynthetically. These target OA derivatives show antibacterial activity against Staphylococcus strains in vitro and in vivo. Among them, derivative c17 was the most promising antibacterial agent while compared with the positive control of norfloxacin, especially against methicillin-resistant Staphylococcus aureus (MRSA) in vitro. In addition, derivative c17 also showed remarkable efficacy against MRSA-infected murine skin model, leading to a significant reduction of bacterial counts during this in vivo study. Furthermore, some preliminary studies indicated that derivative c17 could effectively inhibit and eradicate the biofilm formation, disrupt the integrity of the bacterial cell membrane. Moreover, derivative c17 showed low hemolytic activity and low toxicity to mammalian cells of NIH 3T3 and HEK 293T. These aforementioned findings strongly support the potential of novel indole-benzosulfonamide OA derivatives as anti-MRSA agents.

Asunto(s)

Antibacterianos , Diseño de Fármacos , Indoles , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Ácido Oleanólico , Sulfonamidas , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Ratones , Humanos , Animales , Relación Estructura-Actividad , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/síntesis química , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Estructura Molecular , Células HEK293 , Células 3T3 NIH , Biopelículas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Infecciones Estafilocócicas/tratamiento farmacológico

RESUMEN

From the root barks of a Central African tree Millettia dubia De Wild. (Fabaceae), ten previously undescribed oleanane-type glycosides were isolated by various chromatographic protocols. Their structures were elucidated by spectroscopic methods, mainly 2D NMR experiments and mass spectrometry, as mono- and bidesmosidic glycosides of mesembryanthemoidigenic acid, hederagenin and oleanolic acid. The stimulation of the sweet taste receptor TAS1R2/TAS1R3 by these glycosides was evaluated, and structure/activity relationships were proposed. Two of them showed an agonist effect on TAS1R2/TAS1R3.

Asunto(s)

Glicósidos , Ácido Oleanólico , Receptores Acoplados a Proteínas G , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Glicósidos/química , Glicósidos/farmacología , Glicósidos/aislamiento & purificación , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Humanos , Millettia/química , Corteza de la Planta/química , Raíces de Plantas/química

RESUMEN

Chemotherapy remains one of the most commonly used strategies in cancer treatment but suffers from damages to healthy tissues and organs. How to precisely co-deliver two or more drugs with different mechanisms of action to the tumors for synergistic function is a challenge for chemotherapy. Herein, Oleanolic acid (OA)-conjugated Hyaluronic acid self-assembled nano-micelles loaded with Doxorubicin (DOX) (HSO NPs/DOX) were constructed for CD44 positive cancer targeted codelivery of DOX and OA. HSO NPs/DOX exhibited reduction triggered drug release under high concentration of glutathione, more efficient uptake by 4T1 breast cancer cells than free DOX leading to higher cytotoxicity, pro-apoptotic, and migration inhibitory activities against 4T1 cells. The ex vivo biodistribution experiment demonstrated more HSO NPs/DOX were accumulated in the tumor tissues than free DOX and less in the non-tumor tissues after injections in 4T1 tumor bearing mice. More importantly, synergistic anti-tumor effects of DOX and OA were obtained using HSO NPs/DOX in 4T1 breast tumor-bearing mice and toxicity of DOX to liver and heart were circumvented through regulating the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Silent Information Regulator 1 (Sirt1) expressions. Taken together, HSO NPs/DOX may become a promising codelivery system for chemotherapeutics in cancer therapy.

Asunto(s)

Doxorrubicina , Ácido Hialurónico , Micelas , Ácido Oleanólico , Profármacos , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/administración & dosificación , Ácido Oleanólico/farmacocinética , Animales , Ácido Hialurónico/química , Profármacos/farmacología , Profármacos/química , Ratones , Línea Celular Tumoral , Femenino , Nanopartículas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Distribución Tisular , Portadores de Fármacos/química , Liberación de Fármacos , Humanos , Apoptosis/efectos de los fármacos

RESUMEN

The pentacyclic triterpenes represent a significant class of plant bioactives with a variety of structures and a wide array of biological activities. These are biosynthetically produced via the mevalonate pathway although occasionally mixed pathways may also occur to introduce structural divergence. Oleanolic acid is one of the most explored bioactive from this class of compounds and possesses a broad spectrum of pharmacological and biological activities including liver protection, anti-cancer, atherosclerosis, anti-inflammation, antibacterial, anti-HIV, anti-oxidative, anti-diabetic etc. This review provides an overview of the latest research findings, highlighting the versatile medicinal and biological potential of oleanolic and its future prospects.

Asunto(s)

Ácido Oleanólico , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Humanos , Animales , Estructura Molecular

RESUMEN

BACKGROUND: The therapeutic strategies for acute ischemic stroke were faced with substantial constraints, emphasizing the necessity to safeguard neuronal cells during cerebral ischemia to reduce neurological impairments and enhance recovery outcomes. Despite its potential as a neuroprotective agent in stroke treatment, Chikusetsu saponin IVa encounters numerous challenges in clinical application. RESULT: Brain-targeted liposomes modified with THRre peptides showed substantial uptake by bEnd. 3 and PC-12 cells and demonstrated the ability to cross an in vitro blood-brain barrier model, subsequently accumulating in PC-12 cells. In vivo, they could significantly accumulate in rat brain. Treatment with C-IVa-LPs-THRre notably reduced the expression of proteins in the P2RX7/NLRP3/Caspase-1 pathway and inflammatory factors. This was evidenced by decreased cerebral infarct size and improved neurological function in MCAO rats. CONCLUSION: The findings indicate that C-IVa-LPs-THRre could serve as a promising strategy for targeting cerebral ischemia. This approach enhances drug concentration in the brain, mitigates pyroptosis, and improves the neuroinflammatory response associated with stroke.

Asunto(s)

Barrera Hematoencefálica , Accidente Cerebrovascular Isquémico , Liposomas , Fármacos Neuroprotectores , Piroptosis , Ratas Sprague-Dawley , Saponinas , Animales , Saponinas/farmacología , Saponinas/química , Piroptosis/efectos de los fármacos , Ratas , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Liposomas/química , Masculino , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Células PC12 , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo

RESUMEN

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant number of researchers have synthesized a variety of analogues of OA by modifying its structure with the intention of creating more potent biological agents and improving its pharmaceutical properties. In recent years, chemical and enzymatic techniques have been employed extensively to investigate and modify the chemical structure of OA. This review presents recent advancements in medical chemistry for the structural modification of OA, with a special focus on the biotransformation, semi-synthesis and relationship between the modified structures and their biopharmaceutical properties.

Asunto(s)

Ácido Oleanólico , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/síntesis química , Ácido Oleanólico/metabolismo , Humanos , Biotransformación , Relación Estructura-Actividad , Estructura Molecular , Animales

RESUMEN

Ursolic acid has gradually attracted much attention due to its unique pharmacological activities and valuable market value in recent years. Currently, ursolic acid is mostly extracted from loquat leaves, but the plant extraction method has low yield and high cost, and chemical synthesis is not readily available, so the biosynthesis method provides a new source for ursolic acid. α-amyrin acts as the main precursor for the synthesis of ursolic acid, and its yield is positively correlated with ursolic acid yield. Oxidosqualene cyclase(OSC) belongs to a multigene family which can catalyze the common precursor 2,3-oxidosqualene to generate different types of triterpene backbones, and plays a decisive role in the synthesis of triterpenoids. However, there are fewer reported key genes catalyzing the synthesis of α-amyrin in medicinal plants, and the yield and proportion of α-amyrin in the catalyzed products have always been a focus of research. In this study, ItOSC2, MdOSC1, AaOSC2 and CrAS, four enzymes capable of catalyzing the production of α-amyrin from 2,3-oxidosqualene, were cloned from Iris tectorum, Malus domestica, Artemisia annua and Catharanthus roseus, subject to sequence alignment and phylogenetic tree analyses, and transformed into Saccharomyces cerevisiae as plasmids. After 7 days of fermentation, the yield and proportions of α-amyrin, ß-amyrin and ergosterol were measured. Finally, AaOSC2 with the best ability to catalyze the generation of α-amyrin was filtered out, providing a key gene element for the later construction of engineered yeast strains with high production of α-amyrin and ursolic acid.

Asunto(s)

Transferasas Intramoleculares , Ácido Oleanólico , Transferasas Intramoleculares/genética , Transferasas Intramoleculares/metabolismo , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/biosíntesis , Clonación Molecular , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Triterpenos/metabolismo , Triterpenos/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/metabolismo , Filogenia , Triterpenos Pentacíclicos

RESUMEN

Natural products have always played an important role in pharmacotherapy, helping to control pathophysiological processes associated with human disease. Thus, natural products such as oleanolic acid (OA), a pentacyclic triterpene that has demonstrated important activities in several disease models, are in high demand. The relevant properties of this compound have motivated re-searchers to search for new analogues and derivatives using the OA as a scaffold to which new functional groups have been added or modifications have been realized. OA and its derivatives have been shown to be effective in the treatment of inflammatory processes, triggered by chronic diseases or bacterial and viral infections. OA and its derivatives have also been found to be effective in diabetic disorders, a group of common endocrine diseases characterized by hyperglycemia that can affect several organs, including the liver and brain. This group of compounds has been reported to exhibit significant bioactivity against cancer processes in vitro and in vivo. In this review, we summarize the bioactive properties of OA and its derivatives as anti-inflammatory, anti-bacterial, antiviral, anti-diabetic, hepatoprotective, neuroprotective, and anticancer agents.

Asunto(s)

Ácido Oleanólico , Ácido Oleanólico/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Humanos , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antivirales/farmacología , Antivirales/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antibacterianos/farmacología , Antibacterianos/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química

RESUMEN

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds' Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC50 value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

Asunto(s)

Antineoplásicos , Antioxidantes , Ácido Oleanólico , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad Cuantitativa , Dimerización , Supervivencia Celular/efectos de los fármacos

RESUMEN

Pentacyclic triterpenes have attracted much attention because of their many bioactivities, but their bioaccessibility is low. Oleanolic acid (OA) was used in this study as a typical edible pentacyclic triterpene. In this work, we proposed an OA interfacial delivery model based on W/O Pickering emulsion, and investigated the effects of different oil types on the emulsion properties and OA bioaccessibility of the OA W/O Pickering emulsion interfacial delivery system (EIDS). Medium chain triglyceride (MCT), long chain triglycerides (LCT) and MCT/LCT (1:1, w/w) were selected as carrier oils for the preparation of emulsions, respectively. The results showed that the emulsions formed from LCT had smaller particle sizes, which increased the deformation resistance of the emulsions and exhibited good stability during the simulated in vitro digestion. The extent of free fatty acid (FFA) release during oil digestion was MCT (103.32 ± 3.74 %) > M/L (97.89 ± 2.89 %) > LCT (71.41 ± 6.64 %). Of interest, the bioaccessibility of OA was influenced by the carrier oil: LCT (59.34 ± 2.55 %) > M/L (47.35 ± 6.25 %) > MCT (13.11 ± 1.40 %) ＞ PBS (7.11 ± 1.74 %), and such a difference was mainly attributed to the greater solubilisation of OA in mixed micelles consisting of long-chain fatty acids. In summary, the size of hydrophobic domains in the mixed micelles produced a greater effect than the effect of FFA release on OA bioaccessibility. This study provides a theoretical basis for the interfacial delivery of OA and the enhancement of OA bioaccessibility based on W/O Pickering emulsions with different oil types.

Asunto(s)

Disponibilidad Biológica , Emulsiones , Ácido Oleanólico , Tamaño de la Partícula , Triglicéridos , Emulsiones/química , Ácido Oleanólico/química , Ácido Oleanólico/farmacocinética , Triglicéridos/química , Digestión , Ácidos Grasos no Esterificados/química , Humanos