RESUMO
Leishmaniasis is the most important emerging and uncontrolled infectious disease and the second cause of death among parasitic diseases, after Malaria. One of the main problems concerning the control of infectious diseases is the increased resistance to usual drugs. Overexpression of P-glycoprotein (Pgp)-like transporters represents a very efficient mechanism to reduce the intracellular accumulation of drugs in cancer cells and parasitic protozoans, thus conferring a multidrug resistance (MDR) phenotype. Pgps are active pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. The inhibition of the activity of these proteins represents an interesting way to control drug resistance both in cancer and in infectious diseases. Most conventional mammalian Pgp-MDR modulators are ineffective in the modulation of Pgp activity in the protozoan parasite Leishmania. Consequently, there is a necessity to find effective modulators of Pgp-MDR for protozoan parasites. In this review we describe a rational strategy developed to find specific Pgp-MDR modulators in Leishmania, using natural and semisynthetic dihydro-beta-agarofuran sesquiterpenes from Celastraceae plants. A series of these compounds have been tested on a MDR Leishmania tropica line overexpressing a Pgp transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all of these natural compounds showed potent reversal activity with different degrees of selectivity and a significant low toxicity. The three-dimensional quantitative structure-activity relationship using the comparative molecular similarity indices analysis (CoMSIA), was employed to characterize the requirements of these sesquiterpenes as modulators at Pgp-like transporter in Leishmania.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Medicamentos/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Leishmania/fisiologia , Sesquiterpenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacocinética , Antiprotozoários/farmacologia , Celastraceae/química , Humanos , Leishmaniose/tratamento farmacológico , Leishmaniose/epidemiologia , Estrutura Molecular , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/fisiologia , Sesquiterpenos/químicaRESUMO
Isonuatigenin-3-O-beta-solatriose (1) was isolated from the roots of Solanum sisymbriifolium. Its structure was determined by spectroscopic methods.
Assuntos
Fitoterapia , Extratos Vegetais/química , Solanum , Humanos , Estrutura Molecular , Raízes de Plantas , Saponinas/químicaRESUMO
BACKGROUND: Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. MATERIALS AND METHODS: Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. RESULTS: Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 µM. Nine of these were potent antiproliferative agents (IC50 <10 µM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. CONCLUSIONS: The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.
Assuntos
Antineoplásicos/farmacologia , Colina Quinase/antagonistas & inibidores , Adenocarcinoma/metabolismo , Animais , Antineoplásicos/química , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos , Linhagem Celular Tumoral , Proliferação de Células , Células HT29 , Humanos , Indolquinonas/química , Concentração Inibidora 50 , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Fosfatidilcolinas/química , Proteínas Recombinantes/química , Triterpenos/químicaRESUMO
Abstract: Protozoan parasites are responsible for important diseases that threaten the lives of nearly one-quarter of the human population world-wide. Among them, leishmaniasis has become the second cause of death, mainly due to the emergence of parasite resistance to conventional drugs. P-glycoprotein (Pgp)-like transporters overexpression is a very efficient mechanism to reduce the intracellular accumulation of many drugs in cancer cells and parasitic protozoans including Plasmodium and Leishmania, thus conferring a multidrug resistance (MDR) phenotype. Therefore, there is a great clinical interest in developing inhibitors of these transporters to overcome such a resistance. Pgps are active pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins, and consist of two homologous halves, each containing a transmembrane domain (TMD) involved in drug efflux, and a cytosolic nucleotide-binding domain (NBD) responsible for ATP binding and hydrolysis. Most conventional cancer MDR modulators interact with the drug-binding sites on the TMDs of Pgps, but they are also usually transported and the required concentrations for a permanent inhibition produce subsequent side-effects that hamper their clinical use. Besides, they only poorly modulate the resistance in protozoan parasites. We review here a rational strategy developed to overcome the MDR phenotype in Leishmania, consisting in: i) the selection of an MDR Leishmania tropica line that overexpresses a Pgp-like transporter; ii) the use of their cytosolic NBDs as new pharmacological targets; iii) the search of new natural compounds that revert the MDR phenotype in Leishmania by binding to the TMDs; iv) the combination of subdoses of the above selected modulators directed to both targets in the transporter, NBDs and TMDs, to accumulate their reversal effects while diminishing their toxicity. In this way, we have reverted the MDR phenotype in Leishmania, including the resistance to the most promising new antileishmania agents, the alkyl-lysophospholipids. This approach might be extrapolated to be used in other eukaryotic cells.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Leishmania/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Sítios de Ligação/genética , Resistência a Múltiplos Medicamentos/genética , Flavonoides/química , Flavonoides/farmacologia , Humanos , Leishmania/genética , Leishmania/metabolismo , Leishmaniose/tratamento farmacológico , Estrutura Molecular , Fenótipo , Transporte Proteico , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
The effects produced by nine dihydro-beta-agarofuran sesquiterpenes isolated from Crossopetalum tonduzii (1-8) and Maytenus macrocarpa (9) (Celastraceae) on the reversion of the resistant phenotype on a multidrug-resistant Leishmania line and their binding to recombinant C-terminal nucleotide-binding domain of Leishmania P-glycoprotein-like transporter were studied. The structures of the new compounds (1-5) were elucidated by spectroscopic methods, including (1)H-(13)C heteronuclear correlation (HMQC), long-range correlation spectra with inversal detection (HMBC), ROESY experiments, and chemical correlations. The absolute configuration of one of them (1) was determined by CD studies. The structure-activity relationship is discussed.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Daunorrubicina/farmacologia , Leishmania tropica/efeitos dos fármacos , Rosales/química , Sesquiterpenos/síntese química , Tripanossomicidas/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Dicroísmo Circular , Resistência a Múltiplos Medicamentos , Escherichia coli/metabolismo , Leishmania tropica/metabolismo , Ligação Proteica , Sesquiterpenos/química , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Tripanossomicidas/farmacologiaRESUMO
Parasite resistance to drugs has emerged as a major problem in current medicine, and therefore, there is great clinical interest in developing compounds that overcome these resistances. In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation, and biological activity of dihydro-beta-agarofuran sesquiterpenes from the roots of Maytenus magellanica (1-14) and M. chubutensis (14-17). This type of natural products may be considered as privileged structures. The structures of 10 new compounds, 1, 3, 6-9, and12-15, were determined by means of (1)H and (13)C NMR spectroscopic studies, including homonuclear (COSY and ROESY) and heteronuclear correlation experiments (HMQC and HMBC). The absolute configurations of eight hetero- and homochromophoric compounds, 1, 3,6-9, 12, and 13, were determined by means of CD studies. Fourteen compounds, 1-3 and 6-16, have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. From this series, 1, 2, 3, 14, and 15 showed potent activity, 1 being the most active compound. The structure-activity relationships of the different compounds are discussed.
Assuntos
Leishmania tropica/efeitos dos fármacos , Maytenus/química , Sesquiterpenos/farmacologia , Triterpenos/farmacologia , Tripanossomicidas/farmacologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Dicroísmo Circular , Resistência a Múltiplos Medicamentos , Fluoresceínas/metabolismo , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Raízes de Plantas/química , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/isolamento & purificação , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
A bioactivity guided fractionation, using KB cells and brine shrimp assays, of the methanolic extract from the leaves of Picramnia antidesma yielded two known anthraquinones, aloe-emodin and aloe-emodin anthrone, and three new aloe-emodin C-glycosides, named picramnioside A, picramnioside B and picramnioside C. Structures were established by spectroscopic methods (UV, IR, mass spectrometry, 1H and 13C and 2D NMR including COSY 45, HMQC, HMBC and ROESY). CD was used to establish the absolute configuration of the picramniosides.
Assuntos
Antraquinonas/isolamento & purificação , Glicosídeos/isolamento & purificação , Árvores/química , Animais , Antraquinonas/química , Antraquinonas/farmacologia , Artemia , Linhagem Celular , Glicosídeos/química , Glicosídeos/farmacologia , Análise EspectralRESUMO
Seven species of the genus Argyranthemum were studied for antimicrobial and cytotoxic activities. Argyranthemum adauctum, A. foeniculaceum and A. frutescens showed antimicrobial activity against Gram-positive and Gram-negative and cytotoxic activity against HeLa and Hep-2 cell lines. Two new acetylenic compounds, frutescinol isovalerate and 3'-demethyl frutescinol isovalerate, were isolated from A. frutescens and their structures elucidated by spectroscopic studies.
Assuntos
Antibacterianos/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Extratos Vegetais/toxicidade , Plantas Medicinais , Carcinoma de Células Escamosas , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/farmacologia , Especificidade da Espécie , Células Tumorais CultivadasRESUMO
The new phenols 6-oxo-tingenol, 3-O-methyl-6-oxo-tingenol and 6-oxo-iguesterol were isolated from the root bark of Maytenus canariensis. Their structures were determined by 1H and 13C NMR spectroscopic studies, including HMQC, HMBC, DEPT and ROESY and chemical transformations. The synthesis of 6-oxo-tingenol was achieved from tingenone. These compounds exhibit antibiotic activity against Gram-positive bacteria.
Assuntos
Antibacterianos/isolamento & purificação , Raízes de Plantas/química , Plantas Medicinais/química , Terpenos/isolamento & purificação , Antibacterianos/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Prótons , Terpenos/químicaRESUMO
Thirty four crude extracts of Panamanian plants, from nine species of Celastraceae and Lamiaceae, were assayed for xanthine oxidase (XO) inhibitory activity. The enzymatic activity was estimated by measuring the increase in absorbance at 290 nm due to uric acid formation. Eighty five percent of the crude extracts were found to possess XO inhibitory activity at 50 micrograms/ml and all the extracts of the species from Lamiaceae were active even at 1 micrograms/ml. The ethanol extracts of Hyptis obtusiflora Presl ex Benth. (Lamiaceae) and H. lantanaefolia Poit. (Lamiaceae) exhibited the highest activity with an inhibition of approximately 40% at 1 micrograms/ml.
Assuntos
Extratos Vegetais/farmacologia , Plantas Medicinais , Xantina Oxidase/antagonistas & inibidores , Etanol/química , Panamá , Extratos Vegetais/uso terapêutico , Padrões de Referência , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Ácido Úrico/metabolismoRESUMO
A series of lignans fromBupleurum salicifolium Soland (Umbelliferae) were tested for nematostatic activity on the cysts and freed secondstage juveniles of the potato cyst nematodesGlobodera rostochiensis andG. pallida. None of the six lignans tested-bursehernin, matairesinol, syringaresinol, the novel product buplerol, guayarol, and a derivative, nortrachelogenin triacetate-showed nematicidal activity in an in vitro analysis with second-stage juveniles, but significant differences were noted when the lignans were assayed for nematostatic activity as cyst hatching inhibitors. Bursehernin and matairesinol showed the greatest activity, at concentrations of 50 ppm. This is the first known instance of a natural product inhibiting the hatch of the nematodeG. pallida. The HID (hatching inhibiting dose) of bursehernin was estimated, and some conclusions were drawn about the structure-activity relationships of the lignans under study.
RESUMO
Three new terpenoids, xuxuarine Ealpha (1), a triterpene dimer based on two pristimerin units, and two sesquiterpenoids with a dihydro-beta-agarofuran skeleton (2 and 3) were isolated from Maytenus blepharodes. Their structures were elucidated on the basis of spectral analysis, including homonuclear and heteronuclear correlation NMR experiments (COSY, ROESY, HMQC, and HMBC). The absolute configurations of 1 and 2 were determined by CD studies.
Assuntos
Plantas Medicinais/química , Terpenos/isolamento & purificação , Estrutura Molecular , Análise Espectral , Terpenos/químicaRESUMO
Two novel trimers, triscutins A and B (1 and 2), based on pristimerin triterpene units, were isolated and characterized from Maytenus scutioides. Their structures were determined on the basis of spectroscopic evidence, including 1H-13C heteronuclear correlation (HMQC), long-range correlation with inverse detection (HMBC), and ROESY NMR experiments; and their absolute configurations, by means of CD studies. Compounds 1 and 2 were assayed for antimicrobial and cytotoxic activities, and their possible biosynthetic route is proposed.
Assuntos
Anti-Infecciosos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Antibacterianos , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Bactérias/efeitos dos fármacos , Candida/efeitos dos fármacos , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , América do Sul , Triterpenos/farmacologia , Células Tumorais CultivadasRESUMO
Five new sesquiterpenes (1-5) with a dihydro-beta-agarofuran skeleton were isolated from Crossopetalum tonduzii. Their structures were elucidated by means of 1H and 13C NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments (COSY, ROESY, HMQC, and HMBC). The absolute configurations of 1 and 2 were determined by CD studies and chemical correlation. Compounds 1-3 were assayed against Spodoptera littoralis in an election test and showed low insect-antifeedant activity.
Assuntos
Comportamento Alimentar/efeitos dos fármacos , Plantas/química , Sesquiterpenos/isolamento & purificação , Spodoptera/fisiologia , Animais , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Panamá , Extratos Vegetais/química , Folhas de Planta/química , Sesquiterpenos/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
By antimicrobial and cytotoxic-guided fractionation, a bioactive norquinone-methide triterpene, 15 alpha-hydroxypristimerin, was isolated from a South American medicinal plant, Maytenus scutioides. Its structure was determined on the basis of spectroscopic evidence. Successful chemical transformation of pristimerin to netzahualcoyene indicates that the 15-hydroxy compounds seems to be a possible percursor of 14(15)-ene-quinone-methide-triterpenoids in the biogenetic pathway.
Assuntos
Antibacterianos/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Análise Espectral , Triterpenos/química , Triterpenos/farmacologia , Células Tumorais CultivadasRESUMO
The new nortriterpene methylene quinones amazoquinone (1) and (7S, 8S)-7-hydroxy-7,8-dihydro-tingenone (2), and the new norphenolic triterpenes 7,8-dihydro-6-oxo-tingenol (3), 23-nor-6-oxo-tingenol (4), and 23-oxo-iso-tingenone (5) were isolated from Maytenus amazonica. Their structures were elucidated by spectroscopic methods. Compounds 1, 2, 3, and 5 showed low antitumor activity against four cancer cell lines.
Assuntos
Antineoplásicos Fitogênicos/química , Plantas Medicinais/química , Quinonas/química , Triterpenos/química , Aldeído Redutase/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos DBA , Peru , Quinonas/isolamento & purificação , Quinonas/farmacologia , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Células Tumorais CultivadasRESUMO
A set of friedelane triterpenoids has been isolated from the stem bark exudates of Maytenus macrocarpa. It includes a new friedelan triterpene (1), together with the known compounds friedelin, 3-oxo-29-hydroxyfriedelane, 3-oxofriedelan-25-al, and canophyllol. The structures of these compounds were elucidated by spectroscopic and chemical evidence. Complete 1H and 13C assignments were achieved by 2D NMR spectroscopy. The new compound showed weak activity against aldose reductase. It did not display antitumor activity against P-388 lymphoid neoplasm, A-549 human lung carcinoma, HT-29 human colon carcinoma, or MEL-28 human melanoma cell lines.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Aldeído Redutase/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos DBA , Epiderme Vegetal/química , Triterpenos/farmacologia , Células Tumorais CultivadasRESUMO
The activity of netzahualcoyone on Bacillus subtilis and Escherichia coli was studied. The product inhibited the respiration of intact cells of B. subtilis but had no effect on the respiration of E. coli. However, when preparations of sonically disrupted cells were examined, inhibitory activity on both bacteria was observed.
Assuntos
Antibacterianos/farmacologia , Triterpenos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/fisiologia , Bacillus subtilis/ultraestrutura , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Escherichia coli/ultraestrutura , NAD/metabolismo , Oxirredução , Consumo de Oxigênio/efeitos dos fármacos , Extratos Vegetais/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/fisiologia , Saccharomyces cerevisiae/ultraestruturaRESUMO
The aerial parts of Nanodea muscosa, collected in Chile, yielded two new acetylenic acids. Their structures were elucidated by spectroscopic analyses, including 2D NMR techniques, as (13E)-octadec-13-en-11-ynoic acid (1) and (2E)-octadec-2-en-4-ynedioic acid (2). Compound 2 constitutes the first example of a conjugated ene-yne fatty diacid isolated from a natural source. Compounds 1 and 2 did not exhibit toxicity toward a panel of DNA damage checkpoint defective yeast mutants or show affinity for the 5-HT(1A), 5-HT(2A), D(2), and H(1) receptors.
Assuntos
Ácidos Graxos Insaturados/isolamento & purificação , Santalaceae/química , Alcinos , Chile , Dano ao DNA/efeitos dos fármacos , Ácidos Graxos Insaturados/química , Ácidos Graxos Insaturados/farmacologia , Estrutura Molecular , Receptor 5-HT2A de Serotonina , Receptores de Dopamina D2/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Saccharomyces cerevisiae/efeitos dos fármacos , EstereoisomerismoRESUMO
A polyacetylene has been isolated from Bupleurum salicifolium. Its structure and absolute configuration were determined to be 8S-heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol [1] by means of 1H- and 13C-nmr spectroscopic studies, including 1H-13C heteronuclear correlation (HMQC) and long-range correlation spectra with inverse detection (HMBC). Its absolute configuration was determined by application of the Horeau method. This compound exhibited significant antibiotic activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis. Also isolated during this investigation were the known compounds; betulin, herniarin, 6,7,8-trimethoxycoumarin, p-hydroxyphenethyl alcohol, pluviatolide, guamaroline, bursehernin, guayadequiol, kaerophyllin, and matairesinol dimethyl ether.