RESUMO
Breast cancer resistance protein (BCRP) is a protein belonging to the ATP-binding cassette (ABC) transporter superfamily that has clinical relevance due to its multi-drug resistance properties in cancer. BCRP can be associated with clinical cancer drug resistance, in particular acute myelogenous or acute lymphocytic leukemias. The overexpression of BCRP contributes to the resistance of several chemotherapeutic drugs, such as topotecan, methotrexate, mitoxantrone, doxorubicin and daunorubicin. The Food and Drugs Administration has already recognized that BCRP is clinically one of the most important drug transporters, mainly because it leads to a reduction of clinical efficacy of various anticancer drugs through its ATP-dependent drug efflux pump function as well as its apparent participation in drug resistance. This review article aims to summarize the different research findings on marine natural products with BCRP inhibiting activity. In this sense, the potential modulation of physiological targets of BCRP by natural or synthetic compounds offers a great possibility for the discovery of new drugs and valuable research tools to recognize the function of the complex ABC-transporters.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Descoberta de Drogas/tendências , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Conformação ProteicaRESUMO
Panama boasts an expansive mangrove area and stands as one of the most biodiverse countries in America. While mangrove plants have long been utilized in traditional medicine, there are still unstudied species whose potential medicinal applications remain unknown. This study aimed to extract bioactive compounds from Mora oleifera (Triana ex Hemsl.) Ducke, an understudied mangrove species. Through bioassay-guided fractionation of the crude extract, we isolated seven active compounds identified as lupenone (1), lupeol (2), α-amyrin (3), ß-amyrin (4), palmitic acid (5), sitosterol (6), and stigmasterol (7). Compound structures were determined using spectroscopic analyses, including APCI-HR-MS and NMR. Compounds 1-7 displayed concentration-dependent inhibition of the alpha-glucosidase enzyme, with IC50 values of 0.72, 1.05, 2.13, 1.22, 240.20, 18.70, and 163.10 µM, respectively. Their inhibitory activity surpassed acarbose, the positive control (IC50 241.6 µM). Kinetic analysis revealed that all compounds acted as competitive inhibitors. Docking analysis predicted that all triterpenes bonded to the same site as acarbose in human intestinal alpha-glucosidase (PDB: 3TOP). A complementary metabolomic analysis of M. oleifera active fractions revealed the presence of 64 compounds, shedding new light on the plant's chemical composition. These findings suggest that M. oleifera holds promise as a valuable botanical source for developing compounds for managing blood sugar levels in individuals with diabetes.
RESUMO
Many compounds produced by fungi have relevant pharmaceutical applications. The purpose of this study was to collect and isolate endophytic fungi from different regions of Panama and then to test their potential therapeutic activities against Leishmania donovani, Plasmodium falciparum, and Trypanosoma cruzi as well as their anticancer activities in MCF-7 cells. Of the 25 fungal isolates obtained, ten of them had good anti-parasitic potential, showing selective activity against L. donovani; four had significant anti-malarial activity; and three inhibited the growth of T. cruzi. Anticancer activity was demonstrated in four isolates. Of the active isolates, Edenia sp. strain F0755, Xylaria sp. strain F1220, Aspergillus sp. strain F1544, Mycoleptodiscus sp. strain F0194, Phomopsis sp. strain F1566, Pycnoporus sp. strain F0305, and Diaporthe sp. strain F1647 showed the most promise based on their selective bioactivity and lack of toxicity in the assays.
Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos , Fungos/química , Fungos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Leishmania donovani/efeitos dos fármacos , Panamá , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
As part of an ongoing project to identify oligosaccharides which modulate bacterial multidrug resistance, the CHCl(3)-soluble extract from flowers of a Mexican arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded five lipophilic tetrasaccharide inhibitors of Staphylococcusaureus multidrug efflux pumps, murucoidins XII-XVI (1-5). The macrocyclic lactone-type structures for these linear hetero-tetraglycoside derivatives of jalapinolic acid were established by spectroscopic methods. These compounds were tested for in vitro antibacterial and resistance modifying activity against strains of Staphylococcus aureus possessing multidrug resistance efflux mechanisms. Only murucoidin XIV (3) displayed antimicrobial activity against SA-1199B (MIC 32microg/ml), a norfloxacin-resistant strain that over-expresses the NorA MDR efflux pump. The four microbiologically inactive (MIC>512microg/ml) tetrasaccharides increased norfloxacin susceptibility of this strain by 4-fold (8microg/ml from 32microg/ml) at concentrations of 25microg/ml, while murucoidin XIV (3) exerted the same potentiation effect at a concentration of 5microg/ml.
Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Ipomoea/química , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Sequência de Carboidratos , Espectroscopia de Ressonância Magnética , Viabilidade Microbiana/efeitos dos fármacos , Dados de Sequência Molecular , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND: Mangroves plants and their endophytes represent a natural source of novel and bioactive compounds. In our ongoing research on mangrove endophytes from the Panamanian Pacific Coast, we have identified several bioactive endophytic fungi. From these organisms, an isolate belonging to the genus Zasmidium (Mycosphaerellaceae) showed 91.3% of inhibition against α-glucosidase enzyme in vitro. RESULTS: Zasmidium sp. strain EM5-10 was isolated from mature leaves of Laguncularia racemosa, and its crude extract showed good inhibition against α-glucosidase enzyme (91.3% of inhibition). Bioassay-guided fractionation of the crude extract led to obtaining two active fractions: L (tripalmitin) and M (Fungal Tryglicerides Mixture). Tripalmitin (3.75 µM) showed better inhibitory activity than acarbose (positive control, IC50 217.71 µM). Kinetic analysis established that tripalmitin acted as a mixed inhibitor. Molecular docking and molecular dynamics simulations predicted that tripalmitin binds at the same site as acarbose and also to an allosteric site in the human intestinal α-glucosidase (PDB: 3TOP). CONCLUSIONS: Zasmidium sp. strain EM5-10 represents a new source of bioactive substances that could possess beneficial properties for human health.
RESUMO
A reinvestigation of the CHCl 3-soluble extract from flowers of the Mexican medicinal arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded six new pentasaccharides, murucoidins VI-XI (1- 6), as well as the known pescaprein III (7), stoloniferin I (8), and murucoidins I-V (9- 13). Their structures were characterized through the interpretation of their NMR spectroscopic and FABMS data. Compounds 1-6 were found to be macrolactones of three known glycosidic acids identified as simonic acids A and B, and operculinic acid A, with different fatty acids esterifying the same positions, C-2 on the second rhamnose unit and C-4 on the third rhamnose moiety. The lactonization site of the aglycone was placed at C-2 or C-3 of the second saccharide unit. The esterifying residues were composed of two short-chain fatty acids, 2-methylpropanoic and (2S)-methylbutyric acids, and two long-chain fatty acids, n-dodecanoic (lauric) acid and the new (8R)-(-)-8-hydroxydodecanoic acid. For the latter residue, its absolute configuration was determined by analysis of its Mosher ester derivatives. All members of the murucoidin series exerted a potentiation effect of norfloxacin against the NorA overexpressing Staphylococcus aureus strain SA-1199B by increasing the activity 4-fold (8 microg/mL from 32 microg/mL) at concentrations of 5-25 microg/mL. Stoloniferin I (8) enhanced norfloxacin activity 8-fold when incorporated at a concentration of 5 microg/mL. Therefore, this type of amphipathic oligosaccharide could be developed further to provide more potent inhibitors of this multidrug efflux pump.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Ácidos Graxos/isolamento & purificação , Glicosídeos/isolamento & purificação , Ipomoea/química , Proteínas de Membrana Transportadoras/metabolismo , Plantas Medicinais/química , Resinas Vegetais/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Sequência de Carboidratos , Cromatografia Líquida de Alta Pressão , Ácidos Graxos/química , Glicosídeos/química , Proteínas de Membrana Transportadoras/efeitos dos fármacos , México , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Resinas Vegetais/química , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismoRESUMO
Bioactivity-guided fractionation of a MeOH-EtOAc extract from the young leaves of Nectandra lineata (Lauraceae), using a Trypanosoma cruzi bioassay resulted in the isolation of a novel norlignan 3'-methoxy-3,4-methylenedioxy-4',7-epoxy-9-nor-8,5'-neolignan-9'-acetoxy (1), together with the known compound, 3'-methoxy-3,4-methylenedioxy-4'-7-epoxy-9-nor-8,5'-neolignan-7,8'-diene (2). Compounds 1 and 2 were shown to inhibit the growth of T. cruzi epimastigotes in axenic culture.
Assuntos
Alcenos/química , Alcenos/farmacologia , Lauraceae/química , Lignanas/química , Lignanas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Alcenos/isolamento & purificação , Animais , Lignanas/isolamento & purificação , Folhas de Planta/química , Tripanossomicidas/isolamento & purificação , Trypanosoma cruzi/efeitos dos fármacosRESUMO
BACKGROUND: Panama has an extensive mangrove area and it is one of the countries with the highest biodiversity in America. Mangroves are widely used in traditional medicine, nevertheless, there are very few studies that validates their medicinal properties in America. Given the urgent need for therapeutic options to treat several diseases of public health importance, mangrove ecosystem could be an interesting source of new bioactive molecules. This study was designed to evaluate the potential of Pelliciera rhizophorae as a source of bioactive compounds. RESULTS: The present investigation was undertaken to explore the possible antiparasitic potential and α-glucosidase inhibition by compounds derived from the Panamanian mangrove Pelliciera rhizophorae. Bioassay-guided fractionation of the crude extract led to the isolation of ten chemical compounds: α-amyrine (1), ß-amyrine (2), ursolic acid (3), oleanolic acid (4), betulinic acid (5), brugierol (6) iso-brugierol (7), kaempferol (8), quercetin (9), and quercetrin (10). The structures of these compounds were established by spectroscopic analyses including APCI-HR-MS and NMR. Compounds 4 (IC50 = 5.3 µM), 8 (IC50 = 22.9 µM) and 10 (IC50 = 3.4 µM) showed selective antiparasitic activity against Leishmania donovani, while compounds 1 (IC50 = 19.0 µM) and 5 (IC50 = 18.0 µM) exhibited selectivity against Tripanosoma cruzi and Plasmodium falciparum, respectively. Moreover, compounds 1-5 inhibited α-glucosidase enzyme in a concentration-dependent manner with IC50 values of 1.45, 0.02, 1.08, 0.98 and 2.37 µM, respectively. Their inhibitory activity was higher than that of antidiabetic drug acarbose (IC50 217.7 µM), used as a positive control. Kinetic analysis established that the five compounds acted as competitive inhibitors. Docking analysis predicted that all triterpenes bind at the same site that acarbose in the human intestinal α-glucosidase (PDB: 3TOP). CONCLUSIONS: Three groups of compounds were isolated in this study (triterpenes, flavonols and dithiolanes). Triterpenes and flavones showed activity in at least one bioassay (antiparasitic or α-glucosidase). In addition, only the pentacyclic triterpenes exhibited a competitive type of inhibition against α-glucosidase.
RESUMO
Significant inhibition of the coagulant and hemorrhagic effects of Bothrops asper venom was demonstrated by ethanolic extract prepared from the leaves of Brownea rosademonte. In vitro experiments preincubating 5.5 mg of extract kg-1 b.m. for 30 min with a minimum hemorrhagic dose of venom (273.8 ± 16.1 µg of venom kg-1 b.m.) lowered the hemorrhagic activity of the venom alone in CD-1 mice by 51.5 ± 2.6 %. Additionally, 1.7 mg extract L-1 plasma prolonged 5.1 times the plasma coagulation time. Fractionation of the extract led to the isolation of two compounds: ononitol (1) and quercetrin (2). The structure of compounds 1 and 2 was established by spectroscopic analyses, including APCI-HRMS and NMR (1H, 13C, HSQC, HMBC and COSY). A quercetrin concentration of 0.11 µmol L-1 prolonged the plasma coagulation time 2.6 times demonstrating that this compound was one of the active constituents of the Brownea rosademonte extract.
Assuntos
Antivenenos/farmacologia , Venenos de Crotalídeos/antagonistas & inibidores , Fabaceae/química , Extratos Vegetais/farmacologia , Animais , Antivenenos/isolamento & purificação , Coagulação Sanguínea/efeitos dos fármacos , Bothrops , Etanol/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hemorragia/prevenção & controle , Camundongos , Extratos Vegetais/química , Folhas de Planta , Quercetina/análogos & derivados , Quercetina/isolamento & purificação , Quercetina/farmacologia , Análise EspectralRESUMO
Reinvestigation of the CHCl3-soluble extract from the flowers of Ipomoea murucoides, through preparative-scale recycling HPLC, yielded three pentasaccharides of 11-hydroxyhexadecanoic acid, murucoidins XVII-XIX, in addition to the known murucoidin III and V, all of which were characterized by NMR spectroscopy and mass spectrometry. These compounds were found to be macrolactones of the known pentasaccharides simonic acid B and operculinic acid A. The acylating groups corresponded to acetic, (2S)-methyl-butyric, (E)-cinnamic and octanoic acids. The esterification sites were established at the C-2 of the second rhamnose and C-3 and C-4 of the third rhamnose. The aglycone lactonization was placed at C-2 or C-3 of the first rhamnose. Bioassays for modulation of antibiotic activity were performed against multidrug-resistant strains of Staphylococcus aureus, Escherichia coli Rosetta-gami, and two nosocomial pathogens: Salmonella enterica sv. Typhi and Shigella flexneri. The tested glycolipids did not act as cytotoxic (IC50>4 µg/mL) nor as antimicrobial (MIC>128 µg/mL) agents. However, they exerted a potentiation effect on clinically useful antibiotics against the tested bacteria by increasing their antibiotic susceptibility up to four-fold at concentrations of 25 µg/mL.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Ipomoea/química , Lactonas/farmacologia , Oligossacarídeos/farmacologia , Extratos Vegetais/farmacologia , Acilação , Caprilatos/química , Caprilatos/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Infecção Hospitalar/microbiologia , Escherichia coli/efeitos dos fármacos , Esterificação , Flores , Glicosídeos/química , Glicosídeos/farmacologia , Interações Ervas-Drogas , Lactonas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Estrutura Molecular , Oligossacarídeos/química , Extratos Vegetais/química , Salmonella enterica/efeitos dos fármacos , Shigella flexneri/efeitos dos fármacosRESUMO
With the combined goal of finding the best anti-parasitic and anti-cancer activities as well as isolating the bioactive agents and studying their structures and biological properties, we proceeded to perform a small-scale cultivation of Aspergillus sp. strain F1544 using Potato Dextrose, Malt Extract, Czapek Dox and Eight Vegetables media. From the more promising extracts (obtaining using potato dextrose and czapek dox media in large scale) of this fungus, we isolated the five compounds: pseurotin A (1), 14-norpseurotin A (2), FD-838 (3), and pseurotin D (4), and fumoquinone B (5). All compounds showed good antileishmanial and moderate anticancer activities.
Assuntos
Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Aspergillus/química , Antineoplásicos/química , Antiprotozoários/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Humanos , Leishmania donovani/efeitos dos fármacos , Estrutura Molecular , Plasmodium/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Purification of a CHCl3-soluble extract from seeds of the Mexican medicinal arborescent morning glory, Ipomoea intrapilosa, by means of preparative-scale recycling HPLC, yielded seven new resin glycosides, intrapilosins I-VII (1-7). Their structures were established through the interpretation of their NMR spectroscopic and FABMS data. All pentasaccharides were found to be macrolactones of the known operculinic acid A with different fatty acids esterifying the same positions: C-2 on the second rhamnose unit and C-3 and C-4 on the third rhamnose moiety. The lactonization site of the aglycon could be placed at C-2 of the second saccharide. The fatty acid components of 1-7 were identified as (+)-(2S)-methylbutanoic, octanoic (caprylic), dodecanoic (lauric), and trans-cinnamic. The less common (-)-(2R)-methylbutanoic acid was also isolated as one of the saponification-liberated residues from intrapilosin IV (4). The presence of the (2R)- and (2S)-methylbutanoyl enantiomers bonded to the same oligosaccharide core in intrapilosins IV (4) and V (5) represents an example of diastereoisomerism due to a chiral esterifying moiety in the resin glycoside mixtures of a morning glory species.
Assuntos
Ipomoea/química , Oligossacarídeos/química , Oligossacarídeos/isolamento & purificação , Plantas Medicinais/química , Resinas Vegetais/química , Glicosídeos/análise , México , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Sementes/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The CHCl(3)-soluble extract from the flowers of the Mexican medicinal plant Ipomoea murucoides, through preparative-scale recycling HPLC, yielded murucoidins I-V (1-5), which are new pentasaccharides of jalapinolic acid, as well as the known stoloniferin I (6). Saponification of the crude resin glycoside mixture yielded two glycosidic acids, simonic acid B (9) and operculinic acid A (10), and their esterifying residues were composed of the two short-chain fatty acids, 2-methylpropanoic and (2S)-methylbutyric acids. All the isolated compounds (1-6) were characterized through high-field NMR spectroscopy. Compound 4 exhibited marginal cytotoxicity against Hep-2 cells (ED(50) 4 microg/mL).
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Glicosídeos/isolamento & purificação , Ipomoea/química , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Sequência de Carboidratos , Ensaios de Seleção de Medicamentos Antitumorais , Flores/química , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , México , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Resinas Vegetais/química , Células Tumorais CultivadasRESUMO
Many compounds produced by fungi have relevant pharmaceutical applications. The purpose of this study was to collect and isolate endophytic fungi from different regions of Panama and then to test their potential therapeutic activities against Leishmania donovani, Plasmodium falciparum, and Trypanosoma cruzi as well as their anticancer activities in MCF-7 cells. Of the 25 fungal isolates obtained, ten of them had good anti-parasitic potential, showing selective activity against L. donovani; four had significant anti-malarial activity; and three inhibited the growth of T. cruzi. Anticancer activity was demonstrated in four isolates. Of the active isolates, Edenia sp. strain F0755, Xylaria sp. strain F1220, Aspergillus sp. strain F1544, Mycoleptodiscus sp. strain F0194, Phomopsis sp. strain F1566, Pycnoporus sp. strain F0305, and Diaporthe sp. strain F1647 showed the most promise based on their selective bioactivity and lack of toxicity in the assays (AU)
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