RESUMO
As part of our continuous research for the discovery of bioactive compounds against Trypanosoma cruzi and Leishmania infantum, the alkaloid (6aS)-dicentrine (1) was oxidized to afford (6aS,6S)- (2) and (6aS,6R)- (3) dicentrine-N-oxides. Evaluation of the cytotoxicity against NCTC cells indicated that 2 and 3 are non-toxic (CC50>200 µM) whereas 1 demonstrated CC50 of 52.0 µM. Concerning T. cruzi activity against amastigotes, derivatives 2 and 3 exhibited EC50 values of 9.9 µM (SI>20.2) and 27.5 µM (SI>7.3), respectively, but 1 is inactive (EC50>100 µM). Otherwise, when tested against L. infantum amastigotes, 1 and 3 exhibited EC50 values of 10.3 µM (SI=5.0) and 12.7 µM (SI>15.7), respectively, being 2 inactive (EC50>100 µM). Comparing the effects of positive controls benznidazol (EC50=6.5 µM and SI>30.7) and miltefosine (EC50=10.2 µM and SI=15.2), it was observed a selective antiparasitic activity to diastereomers 2 and 3 against T. cruzi and L. infantum. Considering stereochemical aspects, it was suggested that the configuration of the new stereocenter formed after oxidation of 1 played an important role in the bioactivity against amastigotes of both tested parasites.
Assuntos
Leishmania infantum , Testes de Sensibilidade Parasitária , Trypanosoma cruzi , Animais , Camundongos , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/síntese química , Linhagem Celular , Relação Dose-Resposta a Droga , Leishmania infantum/efeitos dos fármacos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacosRESUMO
Annona crassiflora Mart. is an endemic plant from Brazilian Cerrado (savanna) biome, commonly employed in traditional medicine to treat wounds, diarrhea, and scalp infections. The pulp of the fruits is edible and has a characteristic taste, being employed to prepare sweets like jam, cakes, and ice cream by the people who live in the region of the Cerrado, although the peels are discarded. In this way, the A. crassiflora fruit peels ethanol extract was prepared and subjected to liquid-liquid extraction, which yielded the alkaloidal fraction (CH2Cl2). Subjected to high-performance liquid chromatography separations, this fraction allowed the purification of the aporphine alkaloids stephalagine (1), liriodenine (2), and atherospermidine (3), that were structurally characterized by high-resolution mass spectrometry with electrospray ionization, and nuclear magnetic resonance spectroscopy analyses. Aporphine alkaloids are recognized for their acetylcholinesterase (AChE) inhibitory activity, an important target in Alzheimer's disease therapy. Thus, the ethanol extract, alkaloidal fraction, and compounds1,2,and3were evaluated for acetyl- and butyrylcholinesterase (BChE) inhibitory activities. Compound1(IC50 104.2 µmol L-1) exhibited better BChE inhibitory activity than the standard compound galanthamine (IC50 162.7 µmol L-1), while2had a comparable result(and IC50 167.3 µmol L-1). Furthermore, molecular docking was performed to predict the compound's binding mode to the human AChE at a molecular level. Semiempirical calculation results show that the enthalpy interaction energy (ΔHint) between AChE and BChE active sites and all ligands were favorable for both enzymes, with the ligands interacting even more strongly with AChE, corroborating with IC50 results.
Assuntos
Alcaloides , Annona , Aporfinas , Acetilcolinesterase/metabolismo , Alcaloides/farmacologia , Annona/química , Aporfinas/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Etanol , Humanos , Ligantes , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologiaRESUMO
One new aporphine, dicentrine-ß-N-oxide (1), together with five related known alkaloids dehydrodicentrine (2), predicentrine (3), N-methyllaurotetanine (4), cassythicine (5), and dicentrine (6) were isolated from the leaves of Ocotea puberula (Lauraceae). Antiprotozoal activity of the isolated compounds was evaluated inâ vitro against trypomastigote forms of Trypanosoma cruzi. Among the tested compounds, alkaloid 1 exhibited higher potential with EC50 value of 18.2â µM and reduced toxicity against NCTC cells (CC50 >200â µM - SI>11.0), similar to positive control benznidazole (EC50 of 17.7â µM and SI=10.7). Considering the promising results of dicentrine-ß-N-oxide (1) against trypomastigotes, the mechanism of parasite death caused by this alkaloid was investigated. As observed, this compound reached the plasma membrane electric potential directly after 2â h of incubation and triggered mitochondrial depolarization, which probably leads to trypomastigote death. Therefore, dicentrine-ß-N-oxide (1), reported for the first time in this work, can contribute to future works for the development of new trypanocidal agents.
Assuntos
Aporfinas/farmacologia , Membrana Celular/efeitos dos fármacos , Ocotea/química , Extratos Vegetais/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Aporfinas/química , Aporfinas/isolamento & purificação , Linhagem Celular , Membrana Celular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
Purpose Among alkaloids, abundant secondary metabolites in plants, aporphines constitute a class of compounds with interesting biological activities, including anticancer effects. The present study evaluated the anticancer activities of 14 substances, including four aporphine derivatives acquired through the biomonitoring of (±)-apomorphine hydrochloride total synthesis from 2-phenethylamine and 3,4-dimethoxybenzaldehyde against head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic effects of compounds against a panel of HNSCC cell lines were determined by PrestoBlue cell viability assay, while the genotoxicity of substances was evaluated by micronucleus test. Cell death was detected by flow cytometry (Annexin V/7AAD) and western blot analysis was used to detect the presence of cleaved Caspase-3 molecules. Results The aporphine and isoquinoline derivatives APO, C1, and A5 significantly reduced HNSCC cell viability and promoted DNA damages in these cells. Further, by activating the Caspase-3 pathway, these substances were able to induce apoptosis. Conclusion Our results revealed that APO, C1, and A5 exhibit cytotoxic effects in HNSCC cells. The mechanisms of action appear to be partly via the generation of DNA damages and apoptosis induction through Caspase-3 pathway activation. This study provides preclinical data that suggest a potential therapeutic role for APO, C1, and A5 against head and neck cancer cells.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Aporfinas/química , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Antineoplásicos Fitogênicos/química , Apoptose , Aporfinas/farmacologia , Caspase 3/metabolismo , Proliferação de Células , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Células Tumorais CultivadasRESUMO
Chemical constituents and biological activities of the aerial parts of Piper erecticaule C.DC. have been studied for the first time. Fractionation and purification of the extracts afforded aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), piperolactam D (5), together with terpenoids of ß-sitosterol, ß-sitostenone, taraxerol, and lupeol. The structures of these compounds were obtained by analysis of their spectroscopic data, as well as the comparison with that of reported data. Acetylcholinesterase inhibitory activity revealed that compounds 1 and 3 showed strong AChE inhibitory effects with the percentage inhibition of 75.8% and 74.8%, respectively.
Se estudiaron por primera vez los constituyentes quiÌmicos y actividad bioloÌgica de las partes aeÌreas de Piper erecticaule C.DC. El fraccionamiento y la purificacioÌn de los extractos proporcionaron aristolactama AII (1), aristolactama BII (2), piperolactama A (3), piperolactama C (4), piperolactama D (5), junto con terpenoides de ß-sitosterol, ß-sitostenona, taraxerol, y el lupeol. Las estructuras de estos compuestos se obtuvieron mediante el anaÌlisis de sus datos espectroscoÌpicos, asiÌ como mediante la comparacioÌn con datos ya informados. La actividad inhibidora de la acetilcolinesterasa reveloÌ que los compuestos 1 y 3 mostraron un potente efecto inhibidor de la AChE con un porcentaje de inhibicioÌn del 75.8% y 74.8%, respectivamente.
Assuntos
Aporfinas/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Extratos Vegetais/química , Inibidores da Colinesterase/farmacologia , Piper/química , Alcaloides/farmacologia , Aporfinas/química , Terpenos/isolamento & purificação , Inibidores da Colinesterase/química , Alcaloides Indólicos/química , Alcaloides/química , Lactamas/químicaRESUMO
Cancer is a disease that involves impaired genome stability with a high mortality index globally. Since its discovery, many have searched for effective treatment, assessing different molecules for their anticancer activity. One of the most studied sources for anticancer therapy is natural compounds and their derivates, like alkaloids, which are organic molecules containing nitrogen atoms in their structure. Among them, oxoisoaporphine and sampangine compounds are receiving increased attention due to their potential anticancer effects. Boldine has also been tested as an anticancer molecule. Boldine is the primary alkaloid extract from boldo, an endemic tree in Chile. These compounds and their derivatives have unique structural properties that potentially have an anticancer mechanism. Different studies showed that this molecule can target cancer cells through several mechanisms, including reactive oxygen species generation, DNA binding, and telomerase enzyme inhibition. In this review, we summarize the state-of-art research related to oxoisoaporphine, sampangine, and boldine, with emphasis on their structural characteristics and the relationship between structure, activity, methods of extraction or synthesis, and anticancer mechanism. With an effective cancer therapy still lacking, these three compounds are good candidates for new anticancer research.
Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Aporfinas , Inibidores Enzimáticos , Compostos Heterocíclicos de 4 ou mais Anéis , Naftiridinas , Neoplasias/tratamento farmacológico , Alcaloides/química , Alcaloides/uso terapêutico , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Aporfinas/química , Aporfinas/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Naftiridinas/química , Naftiridinas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Telomerase/antagonistas & inibidores , Telomerase/metabolismoRESUMO
Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.
Assuntos
Aporfinas/administração & dosagem , Hipertensão Renovascular/tratamento farmacológico , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/genética , Animais , Aporfinas/química , Humanos , Hipertensão Renovascular/genética , Hipertensão Renovascular/patologia , Rim/efeitos dos fármacos , Rim/lesões , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Estresse Oxidativo/efeitos dos fármacos , Peumus/química , Ratos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
This first phytochemical study of leaves of Ocotea caudata led to the isolation of ten isoquinoline alkaloids, one of them previously unreported, S-(+)-9-O-demethylnorpreocoteine (1), three known flavonoids, two phenols, two eudesmane type sesquiterpenoids, one proline derivative, one fatty alcohol and a phytosterol. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analyses including HSQC, HMBC, 1H-1H COSY, NOESY, as well as HRESIMS data in addition to comparison with reports in the literature.
Assuntos
Ocotea/química , Compostos Fitoquímicos/química , Folhas de Planta/química , Alcaloides/análise , Alcaloides/química , Animais , Colômbia , Flavonoides/análise , Flavonoides/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Fitoquímicos/análise , Sesquiterpenos/análise , Sesquiterpenos/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Annona crassiflora and Annonaceae plants are known to be used to treat malaria by traditional healers. In this work, the antimalarial efficacy of different fractions of A. crassiflora, particularly acetogenin, alkaloids and flavonoid-rich fractions, was determined in vivo using Plasmodium berghei-infected mice model and toxicity was accessed by brine shrimp assay. The A. crassiflora fractions were administered at doses of 12.5 mg/kg/day in a 4-day test protocol. The results showed that some fractions from woods were rich in acetogenins, alkaloids and terpenes, and other fractions from leaves were rich in alkaloids and flavonoids. The parasitaemia was significantly (p < 0.05, p < 0.001) reduced (57-75%) with flavonoid and alkaloid-rich leaf fractions, which also increased mean survival time of mice after treatment. Our results confirm the usage of this plant in folk medicine as an antimalarial remedy.
Assuntos
Acetogeninas/isolamento & purificação , Acetogeninas/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Annona/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Acetogeninas/química , Alcaloides/química , Animais , Antimaláricos/química , Artemia/efeitos dos fármacos , Modelos Animais de Doenças , Flavonoides/química , Dose Letal Mediana , Malária/tratamento farmacológico , Medicina Tradicional , Camundongos , Estrutura Molecular , Folhas de Planta/química , Plasmodium berghei/efeitos dos fármacosRESUMO
INTRODUCTION: The Unonopsis genus is a promising source of aporphinoid alkaloids, substances with great biological potential. These alkaloids have a well-defined mass spectrometry fragmentation pattern that, together with previous phytochemical knowledge, can guide the isolation of alkaloids not yet described for the genus. OBJECTIVE: Isolate substances not yet described in the Unonopsis genus, guided by alkaloidal profile analyses of stem barks, twigs and leaves of Unonopsis duckei using electrospray ionisation ion-trap tandem mass spectrometry (ESI-IT/MS(n) ). METHODS: Methanolic extracts from stem barks, twigs and leaves were submitted to a liquid-liquid, acid-base partitioning treatment to obtain the alkaloidal fractions. These fractions were analysed by direct infusion into an ESI-IT/MS(n) system. The major alkaloids observed for each fraction were submitted to fragmentation analysis. RESULTS: The MS fragmentation patterns revealed the presence of alkaloids previously reported for Annonaceae, including nornuciferine, anonaine, asimilobine, liriodenine and lysicamine, known for the Unonopsis genus, as well as others that were not yet described for this genus. In this way, the proaporphine alkaloid glaziovine was isolated, as well as a mixture of the aporphine alkaloids glaucine and norglaucine, all described for the first time in the Unonopsis genus. CONCLUSION: Mass spectrometry monitoring was fundamental to prioritise the isolation of substances not yet identified for the Unonopsis genus, dismissing known compounds and simplifying the phytochemical study.
Assuntos
Alcaloides/análise , Annonaceae/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Alcaloides/química , Aporfinas/análise , Dioxóis/análise , Casca de Planta/química , Folhas de Planta/químicaRESUMO
In vitro evaluation of alkaloidal fractions of twigs, barks and leaves from two Unonopsis species, Unonopsis guatterioides R.E. Fr. and Unonopsis duckei R.E. Fr., Annonaceae, against promastigote forms of Leishmania amazonensis revealed these species as sources of substances with promising leishmanicidal potential. All alkaloidal fractions from twigs, barks and leaves of U. guatterioides were classified as highly active, with IC50 1.07, 1.90, and 2.79 mg/mL, respectively. Only the alkaloidal fraction from the twigs of U. duckei was classified as inactive.