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1.
BMC Res Notes ; 14(1): 348, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496958

RESUMO

OBJECTIVE: Papaver decaisnei Hochst. & Steud. Ex Elkan and Papaver glaucum Boiss. & Hausskn. growing wild in Northern Iraq have been historically used for medicinal purposes. In this study, both species were evaluated for their alkaloid content and antimicrobial activities. RESULTS: Alkaloids were extracted and isolated by preparative thin-layer chromatography (TLC). Identification was carried out by comparing spectral data (UV and 1H-NMR) and TLC Rf values with those of authentic samples. Two alkaloids, proapaorphine-type mecambrine and aporphine-type roemerine were isolated from P. decaisnei. Two benzylisoquinoline type alkaloids papaverine (major alkaloid) and palaudine as well as aporphine-type N-methylasimilobine have been obtained in P. glaucum. Both P. glaucum and P. decaisnei extracts revealed strong antimicrobial activity on Pseudomonas aeruginosa ATCC 27853 and Enterococcus faecalis ATCC 29212. Collectively these results indicate that P. glaucum and P. decaisnei are promising sources of alkaloids that could further be investigated for medicinal purposes.


Assuntos
Alcaloides , Anti-Infecciosos , Papaver , Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Cromatografia em Camada Delgada , Extratos Vegetais/farmacologia
2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361040

RESUMO

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02-8.7 µM) and NET inhibitors (IC50 = 0.03-4.6 µM), and exhibited no SERT activity at concentrations < 10 µM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17-0.18 µM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264-356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.


Assuntos
Alcaloides/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Psicotrópicos/química , Pirrolidinas/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Alcaloides/farmacologia , Monoaminas Biogênicas/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Células HEK293 , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Psicotrópicos/farmacologia , Pirrolidinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Inibidores de Captação de Serotonina/química , Inibidores de Captação de Serotonina/farmacologia
3.
J Agric Food Chem ; 69(34): 9754-9763, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415761

RESUMO

Plant viruses and fungi are a serious threat to food security and natural ecosystems. The efficient and environment-friendly control methods are urgently needed to help safeguard such resources. Here, we achieved the efficient synthesis of toad alkaloid dehydrobufotenine in eight steps with an overall yield of 8% from 5-methoxyindole. A series of dehydrobufotenine derivatives were designed, synthesized, and evaluated for their antiviral and fungicidal activities systematically. It was found for the first time that these compounds have good anti-plant virus activities and anti-plant pathogen activities. The antiviral activities of 21 compounds were similar to or better than those of ribavirin. Compounds 12 and 17 displayed better antiviral activities than ningnanmycin which is perhaps the most effective anti-plant virus agent. The antiviral mechanism research study of 12 revealed that it could make 20S CP disk fusion and aggregation. Further molecular docking results showed that there are hydrogen bonds between compounds 12, 17, and tobacco mosaic virus CP. The docking results are consistent with the antiviral activity. These compounds also displayed broad-spectrum fungicidal activities against 14 kinds of fungi, especially for Sclerotinia sclerotiorum. In this work, the synthesis, structure optimization, structure-activity relationship studies, and mode of action research of dehydrobufotenine alkaloids were carried out. It provides a reference for the development of the anti-plant virus agent and anti-plant pathogen agent from toad alkaloids.


Assuntos
Alcaloides , Fungicidas Industriais , Praguicidas , Vírus de Plantas , Vírus do Mosaico do Tabaco , Alcaloides/farmacologia , Antivirais/farmacologia , Ascomicetos , Desenho de Fármacos , Ecossistema , Fungos , Fungicidas Industriais/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
4.
Phytochemistry ; 191: 112903, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34384922

RESUMO

Six new Cephalotaxus alkaloids, including five cephalotaxine-type alkaloids, and one homoerythrina-type alkaloid, along with six known analogues, were isolated from the seeds of Cephalotaxus fortunei. Their structures were elucidated by combination of spectroscopic data analyses, time-dependent density functional theory (TDDFT) ECD calculation, and single-crystal X-ray diffraction. Cephalofortine B represents the first example of C-5 epi-cephalotaxine-type alkaloid. All isolated compounds were tested for cytotoxicities against HCT-116, A375, and SK-Mel-28 cell lines. Cephalofortine E showed moderate activity against HCT-116 cell line, with an IC50 value of 7.46 ± 0.77 µM.


Assuntos
Alcaloides , Antineoplásicos Fitogênicos , Cephalotaxus , Harringtoninas , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Harringtoninas/farmacologia , Mepesuccinato de Omacetaxina , Humanos , Estrutura Molecular , Sementes
5.
Phytochemistry ; 191: 112923, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34454171

RESUMO

Glaucium Mill. comprising 28 species with 78 synonyms, 3 subspecies, and 3 varieties worldwide belongs to the Papaveraceae family. The plants are well known for their different types of alkaloids. In the present study, we attempted to review the chemistry and pharmacology of the alkaloids from the genus Glaucium. For this purpose, the relevant data were collected from different scientific databases including, "Google Scholar", "ISI Web of Knowledge", "PubMed", "Scopus", and available books and e-books. Our results showed that aporphine alkaloids are dominated in the species; however, other types of alkaloids including protopines, benzophenanthridines, benzylisoquinolines, protoberberines, and morphinanes have also been reported from the genus. The pharmacological studies have shown that the alkaloids from Glaucium species have several biological activities of which anti-cancer and anti-cholinesterase effects have been highly reported. Besides, the data indicated that most of the species have been investigated neither phytochemically nor pharmacologically. Glaucium flavum, known as yellow horn poppy, is the most studied species. According to the reports, the plants from this genus have anti-cancer and anti-cholinesterase potentials and can be used as a source for aporphine alkaloids.


Assuntos
Alcaloides , Benzilisoquinolinas , Papaveraceae , Plantas Medicinais , Alcaloides/farmacologia , Benzofenantridinas
6.
J Gen Virol ; 102(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34424155

RESUMO

Infectious bronchitis virus (IBV) is an economically important coronavirus, causing damaging losses to the poultry industry worldwide as the causative agent of infectious bronchitis. The coronavirus spike (S) glycoprotein is a large type I membrane protein protruding from the surface of the virion, which facilitates attachment and entry into host cells. The IBV S protein is cleaved into two subunits, S1 and S2, the latter of which has been identified as a determinant of cellular tropism. Recent studies expressing coronavirus S proteins in mammalian and insect cells have identified a high level of glycosylation on the protein's surface. Here we used IBV propagated in embryonated hens' eggs to explore the glycan profile of viruses derived from infection in cells of the natural host, chickens. We identified multiple glycan types on the surface of the protein and found a strain-specific dependence on complex glycans for recognition of the S2 subunit by a monoclonal antibody in vitro, with no effect on viral replication following the chemical inhibition of complex glycosylation. Virus neutralization by monoclonal or polyclonal antibodies was not affected. Following analysis of predicted glycosylation sites for the S protein of four IBV strains, we confirmed glycosylation at 18 sites by mass spectrometry for the pathogenic laboratory strain M41-CK. Further characterization revealed heterogeneity among the glycans present at six of these sites, indicating a difference in the glycan profile of individual S proteins on the IBV virion. These results demonstrate a non-specific role for complex glycans in IBV replication, with an indication of an involvement in antibody recognition but not neutralisation.


Assuntos
Coronavirus/fisiologia , Polissacarídeos/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Alcaloides/química , Alcaloides/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células Cultivadas , Cromatografia Líquida , Biologia Computacional/métodos , Coronavirus/efeitos dos fármacos , Infecções por Coronavirus/veterinária , Regulação Viral da Expressão Gênica , Glicosilação/efeitos dos fármacos , Vírus da Bronquite Infecciosa/fisiologia , Modelos Moleculares , Conformação Molecular , Peso Molecular , Testes de Neutralização , Oligossacarídeos/química , Oligossacarídeos/metabolismo , Polissacarídeos/química , Doenças das Aves Domésticas/virologia , Transporte Proteico , Espectrometria de Massas por Ionização por Electrospray , Glicoproteína da Espícula de Coronavírus/genética , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
7.
Molecules ; 26(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34443335

RESUMO

The specificity of inhibition by 6,6'-dihydroxythiobinupharidine (DTBN) on cysteine proteases was demonstrated in this work. There were differences in the extent of inhibition, reflecting active site structural-steric and biochemical differences. Cathepsin S (IC50 = 3.2 µM) was most sensitive to inhibition by DTBN compared to Cathepsin B, L and papain (IC50 = 1359.4, 13.2 and 70.4 µM respectively). DTBN is inactive for the inhibition of Mpro of SARS-CoV-2. Docking simulations suggested a mechanism of interaction that was further supported by the biochemical results. In the docking results, it was shown that the cysteine sulphur of Cathepsin S, L and B was in close proximity to the DTBN thiaspirane ring, potentially forming the necessary conditions for a nucleophilic attack to form a disulfide bond. Covalent docking and molecular dynamic simulations were performed to validate disulfide bond formation and to determine the stability of Cathepsins-DTBN complexes, respectively. The lack of reactivity of DTBN against SARS-CoV-2 Mpro was attributed to a mismatch of the binding conformation of DTBN to the catalytic binding site of Mpro. Thus, gradations in reactivity among the tested Cathepsins may be conducive for a mechanism-based search for derivatives of nupharidine against COVID-19. This could be an alternative strategy to the large-scale screening of electrophilic inhibitors.


Assuntos
Alcaloides/farmacologia , Cisteína Proteases/metabolismo , Alcaloides/química , Animais , Antivirais/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Domínio Catalítico , Catepsinas/farmacologia , Linhagem Celular Tumoral , Cisteína Proteases/química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular/métodos , Nuphar/química , Papaína/farmacologia , Extratos Vegetais/farmacologia , Ligação Proteica , SARS-CoV-2/efeitos dos fármacos
8.
Bratisl Lek Listy ; 122(9): 670-679, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34463115

RESUMO

BACKGROUND: Predominant molecules in Peganum harmala leaves were detected using gas chromatography-mass spectrometry (GC-MS). Based on the results of this analysis, most alkaloids, flavonoids and triterpenoids in found P. harmala was compiled from the literature in order to develop and lead the production of effective inhibitor drugs for ACE2, main protease, and RNA dependent RNA polymerase (RdRp) proteins of SARS-CoV-2 virus, which is today's most contagious and deadly disease. AIM: By comparing FDA-approved drugs used in the treatment of COVID-19, we aimed to determine whether the molecules in P. harmala are effective against SARS CoV-2 in silico. RESULTS AND CONCLUSION: P. harmala molecules were selected as drug candidates from the PubChem web tool. Afterwards, molecular docking calculations of these inhibitor molecules were made with Maestro Molecular modeling program by Schrödinger. The comparison of molecules with high inhibitory activities with FDA-approved drugs was made. With molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations, docking calculations of molecules that have high inhibitory activity, were tried to be verified by calculations in the range of 0-100 nanoseconds (Tab. 4, Fig. 6, Ref. 53).


Assuntos
Alcaloides , Peganum , SARS-CoV-2/efeitos dos fármacos , Alcaloides/farmacologia , COVID-19 , Humanos , Simulação de Acoplamento Molecular , Peganum/química , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química
9.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361708

RESUMO

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C-C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.


Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Produtos Biológicos/química , Diterpenos do Tipo Caurano/síntese química , Compostos Heterocíclicos/síntese química , Alcaloides/farmacologia , Alquilação , Antineoplásicos/farmacologia , Azidas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Radicais Livres/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Iodo/química , Lactamas/química , Pirrolidinas/química , Relação Estrutura-Atividade
10.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361712

RESUMO

The genus Maytenus is a member of the Celastraceae family, of which several species have long been used in traditional medicine. Between 1976 and 2021, nearly 270 new compounds have been isolated and elucidated from the genus Maytenus. Among these, maytansine and its homologues are extremely rare in nature. Owing to its unique skeleton and remarkable bioactivities, maytansine has attracted many synthetic endeavors in order to construct its core structure. In this paper, the current status of the past 45 years of research on Maytenus, with respect to its chemical and biological activities are discussed. The chemical research includes its structural classification into triterpenoids, sesquiterpenes and alkaloids, along with several chemical synthesis methods of maytansine or maytansine fragments. The biological activity research includes activities, such as anti-tumor, anti-bacterial and anti-inflammatory activities, as well as HIV inhibition, which can provide a theoretical basis for the better development and utilization of the Maytenus.


Assuntos
Alcaloides/química , Maitansina/análogos & derivados , Maytenus/química , Compostos Fitoquímicos/química , Sesquiterpenos/química , Triterpenos/química , Alcaloides/classificação , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Humanos , Maitansina/isolamento & purificação , Maitansina/farmacologia , Maytenus/metabolismo , Estrutura Molecular , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais , Sesquiterpenos/classificação , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Relação Estrutura-Atividade , Triterpenos/classificação , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
11.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3678-3686, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402292

RESUMO

This study aimed to investigate the antidepressant effects of total alkaloids of Fibraurea recisa in HT22 cells damaged by corticosterone (CORT) in vitro and in a mouse model of chronic unpredictable mild stress (CUMS) as well as the underlying mechanisms.In cellular experiments,the viability of CORT-damaged HT22 cells was detected using cell counting kit-8 (CCK-8),and the cell apoptosis was detected by Hoechst 33258 staining.In animal experiments,C57BL/6N mice were randomly divided into the control group,model group,low (100 mg·kg~(-1)),medium (200 mg·kg~(-1)) and high (400 mg·kg~(-1))-dose of total alkaloids of F.recisa groups,and positive control group.After 21 days of CUMS exposure,their depressive behaviors were observed in behavioral and Morris water maze tests.The serum levels of 5-hydroxytryptamine (5-HT),dopamine (DA),and norepinephrine (NE) were assessed by ELISA.The expression levels of apoptosis-related proteins Bcl-2,Bax and cleaved caspase-3 in HT22 cells and mouse hippocampus were detected by Western blot.The results suggested that total alkaloids of F.recisa alleviated the damage of HT22 cells induced by CORT in a dose-dependent manner.The Hoechst 33258 staining uncovered that total alkaloids of F.recisa better reduced the blue spots and inhibited cell apoptosis.The results of animal experiments showed that total alkaloids of F.recisa significantly improved the depression-like behaviors of mice and increased the serum levels of 5-HT,DA and NE as compared with those in the model group.The Western blot assays revealed a significant up-regulation of Bcl-2 protein expression,but an obvious reduction in Bax and cleaved caspase-3protein expression in the total alkaloids of F.recisa group.In conclusion,total alkaloids of F.recisa inhibited depression possibly by regulating the apoptosis-related protein expression or elevating the monoamine neurotransmitter levels in the brain.


Assuntos
Alcaloides , Depressão , Alcaloides/farmacologia , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico
12.
Behav Neurol ; 2021: 9990375, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447483

RESUMO

Background: Aß deposition abnormally in the mitochondria can damage the mitochondrial respiratory chain and activate the mitochondrial-mediated apoptosis pathway, resulting in AD-like symptoms. Objective: To observe the protective effects of Dendrobium nobile Lindl. alkaloids (DNLA) on Aß 25-35-induced oxidative stress and apoptosis in PC12 cells explore its possible protective mechanisms. Methods: PC12 cells were treated with DNLA with different concentrations (0.035 mg/L, 0.3 mg/L, and 3.5 mg/L) for 6 h, followed by administration with Aß 25-35 (10 µM) for 24 h. MTT assay and flow cytometer observe the effect of DNLA on Aß 25-35-induced cytotoxicity and apoptosis of PC12 cell. Based on the mitochondrial apoptosis pathway to study the antiapoptotic effect of DNLA on this model and its relationship with oxidative stress, flow cytometer detected the level of reactive oxygen species (ROS), and ELISA kits were used to detect superoxide dismutase activity (SOD) and glutathione (GSH) content in cells. The JC-1 fluorescent staining observed the effect of DNLA on the mitochondrial membrane potential (MMP) with inverted immunofluorescence microscopy. Western blot was used to detect the levels of mitochondrial apoptosis pathway-related protein and its major downstream proteins Bax, Bcl-2, cleaved-caspase-9, and cleaved-caspase-3. Results: DNLA can significantly improve the viability and apoptosis rate of PC12 cell damage induced by Aß 25-35. It also can restore the reduced intracellular ROS content and MMP, while SOD activity and GSH content increase significantly. The expression of apoptosis-related protein Bax, cleaved-caspase-9, and cleaved-caspase-3 decreased when the Bcl-2 protein expression was significantly increased. Conclusion: These findings suggest that it can significantly inhibit the apoptosis of PC12 cell damage induced by Aß 25-35. The mechanism may reduce the level of cellular oxidative stress and thus inhibit the mitochondrial-mediated apoptosis pathway.


Assuntos
Alcaloides , Dendrobium , Alcaloides/farmacologia , Animais , Apoptose , Estresse Oxidativo , Células PC12 , Ratos
13.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207059

RESUMO

Diclinanona calycina R. E. Fries popularly known as "envira", is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of D. calycina was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in D. calycina as well as in the genus Diclinanona. The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (1); aporphine, anonaine (2); oxoaporphine, liriodenine (3); benzyltetrahydroisoquinolines, (S)-(+)-reticuline (4); dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (5); (+)-1S,2R-reticuline Nß-oxide (6); and (+)-1S,2S-reticuline Nα-oxide (7); tetrahydroprotoberberine, coreximine (8); and pavine, bisnorargemonine (9). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (10), dichamanetin (11), and a mixture of uvarinol (12) and isouvarinol (13). Compound 5 is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (10), and the mixture of uvarinol (12) and isouvarinol (13), which presented moderate cytotoxic activity against the tested cancer cell lines (<20.0 µg·mL-1) and low cytotoxicity against the non-cancerous cell line MRC-5 (>25.0 µg·mL-1). Dichamanetin (11) showed cytotoxic activity against HL-60 and HCT116 with IC50 values of 15.78 µg·mL-1 (33.70 µmol·L-1) and 18.99 µg·mL-1 (40.56 µmol·L-1), respectively while the mixture of uvarinol (12) and isouvarinol (13) demonstrated cytotoxic activity against HL-60, with an IC50 value of 9.74 µg·mL-1, and HCT116, with an IC50 value of 17.31 µg·mL-1. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound.


Assuntos
Alcaloides/química , Annonaceae/química , Flavonas/química , Isoquinolinas/química , Casca de Planta/química , Alcaloides/farmacologia , Aporfinas/química , Aporfinas/farmacologia , Brasil , Linhagem Celular Tumoral , Dioxóis/química , Dioxóis/farmacologia , Flavanonas/farmacologia , Flavonas/farmacologia , Células HCT116 , Células HL-60 , Células Hep G2 , Humanos , Isoquinolinas/farmacologia , Células MCF-7 , Extratos Vegetais , Folhas de Planta/química
14.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205249

RESUMO

The accumulation and aggregation of α-synuclein (α-syn) is the main pathologic event in Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-Syn-seeded fibril formation and its induced toxicity occupy a major role in PD pathogenesis. Thus, assessing compounds that inhibit this seeding process is considered a key towards the therapeutics of synucleinopathies. Using biophysical and biochemical techniques and seeding-dependent cell viability assays, we screened a total of nine natural compounds of alkaloid origin extracted from Chinese medicinal herbs. Of these compounds, synephrine, trigonelline, cytisine, harmine, koumine, peimisine, and hupehenine exhibited in vitro inhibition of α-syn-seeded fibril formation. Furthermore, using cell viability assays, six of these compounds inhibited α-syn-seeding-dependent toxicity. These six potent inhibitors of amyloid fibril formation and toxicity caused by the seeding process represent a promising therapeutic strategy for the treatment of PD and other synucleinopathies.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , alfa-Sinucleína/antagonistas & inibidores , Amiloide/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Corpos de Lewy/efeitos dos fármacos , Corpos de Lewy/metabolismo , Medicina Tradicional Chinesa/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
15.
J Agric Food Chem ; 69(27): 7565-7571, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34210137

RESUMO

On the basis of our previous studies on the antiviral mechanism against tobacco mosaic virus (TMV) and structure-activity relationship of phenanthroindolizidine alkaloids, a series of 9-substituted tylophorine derivatives targeting TMV RNA were designed, synthesized, and assessed for their anti-TMV activities. The bioassay results indicated that most of these compounds showed good in vivo anti-TMV activities, and some of them displayed higher activity than that of commercial ribavirin. Especially, the anti-TMV activities of compound 3b, 4, and 6 are 2-3 times higher than that of commercial ribavirin, according to EC50 values. In this work, we have demonstrated an effective way to design new inhibitors against plant virus and developed 9-ethoxy methyl tylophorine (4) with excellent anti-TMV activity (in vitro activity, 70.2%/500 µg/mL and 27.1%/100 µg/mL; inactivation activity, 67.7%/500 µg/mL and 30.5%/100 µg/mL; curative activity, 65.3%/500 µg/mL and 30.8%/100 µg/mL; and protection activity, 65.9%/500 µg/mL and 36.0%/100 µg/mL) as a potential plant viral inhibitor.


Assuntos
Alcaloides , Vírus do Mosaico do Tabaco , Alcaloides/farmacologia , Antivirais/farmacologia , Desenho de Fármacos , Indolizinas , Fenantrolinas/farmacologia , Relação Estrutura-Atividade
16.
Molecules ; 26(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204857

RESUMO

Phytochemicals belonging to the group of alkaloids are signature specialized metabolites endowed with countless biological activities. Plants are armored with these naturally produced nitrogenous compounds to combat numerous challenging environmental stress conditions. Traditional and modern healthcare systems have harnessed the potential of these organic compounds for the treatment of many ailments. Various chemical entities (functional groups) attached to the central moiety are responsible for their diverse range of biological properties. The development of the characterization of these plant metabolites and the enzymes involved in their biosynthesis is of an utmost priority to deliver enhanced advantages in terms of biological properties and productivity. Further, the incorporation of whole/partial metabolic pathways in the heterologous system and/or the overexpression of biosynthetic steps in homologous systems have both become alternative and lucrative methods over chemical synthesis in recent times. Moreover, in-depth research on alkaloid biosynthetic pathways has revealed numerous chemical modifications that occur during alkaloidal conversions. These chemical reactions involve glycosylation, acylation, reduction, oxidation, and methylation steps, and they are usually responsible for conferring the biological activities possessed by alkaloids. In this review, we aim to discuss the alkaloidal group of plant specialized metabolites and their brief classification covering major categories. We also emphasize the diversity in the basic structures of plant alkaloids arising through enzymatically catalyzed structural modifications in certain plant species, as well as their emerging diverse biological activities. The role of alkaloids in plant defense and their mechanisms of action are also briefly discussed. Moreover, the commercial utilization of plant alkaloids in the marketplace displaying various applications has been enumerated.


Assuntos
Alcaloides/química , Alcaloides/metabolismo , Fenômenos Fisiológicos Vegetais , Plantas/química , Acilação , Alcaloides/farmacologia , Vias Biossintéticas , Glicosilação , Metilação , Estrutura Molecular , Oxirredução , Compostos Fitoquímicos/química , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia
17.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299015

RESUMO

Synthetic cathinones have gained popularity among young drug users and are widely used in the clandestine market. While the cathinone-induced behavioral profile has been extensively investigated, information on their neuroplastic effects is still rather fragmentary. Accordingly, we have exposed male mice to a single injection of MDPV and α-PVP and sacrificed the animals at different time points (i.e., 30 min, 2 h, and 24 h) to have a rapid readout of the effect of these psychostimulants on neuroplasticity in the frontal lobe and hippocampus, two reward-related brain regions. We found that a single, low dose of MDPV or α-PVP is sufficient to alter the expression of neuroplastic markers in the adult mouse brain. In particular, we found increased expression of the transcription factor Npas4, increased ratio between the vesicular GABA transporter and the vesicular glutamate transporter together with changes in the expression of the neurotrophin Bdnf, confirming the widespread impact of these cathinones on brain plasticity. To sum up, exposure to low dose of cathinones can impair cortical and hippocampal homeostasis, suggesting that abuse of these cathinones at much higher doses, as it occurs in humans, could have an even more profound impact on neuroplasticity.


Assuntos
Alcaloides/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzodioxóis/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentanonas/farmacologia , Pirrolidinas/farmacologia , Ácido gama-Aminobutírico/metabolismo
18.
Molecules ; 26(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279443

RESUMO

Diterpenoid alkaloids are natural compounds having complex structural features with many stereo-centres originating from the amination of natural tetracyclic diterpenes and produced primarily from plants in the Aconitum, Delphinium, Consolida genera. Corals, Xenia, Okinawan/Clavularia, Alcyonacea (soft corals) and marine sponges are rich sources of diterpenoids, despite the difficulty to access them and the lack of availability. Researchers have long been concerned with the potential beneficial or harmful effects of diterpenoid alkaloids due to their structural complexity, which accounts for their use as pharmaceuticals as well as their lousy reputation as toxic substances. Compounds belonging to this unique and fascinating family of natural products exhibit a broad spectrum of biological activities. Some of these compounds are on the list of clinical drugs, while others act as incredibly potent neurotoxins. Despite numerous attempts to prepare synthetic products, this review only introduces the natural diterpenoid alkaloids, describing 'compounds' structures and classifications and their toxicity and bioactivity. The purpose of the review is to highlight some existing relationships between the presence of substituents in the structure of such molecules and their recognised bioactivity.


Assuntos
Alcaloides/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Animais , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Humanos , Testes de Toxicidade
19.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207657

RESUMO

The fungus strain DZ-3 was isolated from twigs of the well-known medicinal plant Eucommia ulmoides Oliver and identified as Aspergillus flavipes. Two new alkaloids, named asperflaloids A and B (1 and 2), together with 10 known compounds (3-12) were obtained from the EtOAc extract of the strain. Interestingly, the alkaloids 1-4 with different frameworks are characterized by the presence of the same anthranilic acid residue. The structures were established by detailed analyses of the spectroscopic data. The absolute configuration of asperflaloids A and B was resolved by quantum chemistry calculation. All compounds were screened for their inhibitions against α-glucosidase and the antioxidant capacities. The results were that compound 3 had an IC50 value of 750.8 µM toward α-glucosidase, and the phenol compounds 7 and 8 exhibited potent antioxidant capacities with IC50 values 14.4 and 27.1 µM respectively.


Assuntos
Alcaloides/química , Antioxidantes/farmacologia , Aspergillus/química , Eucommiaceae/microbiologia , alfa-Glucosidases/química , Alcaloides/farmacologia , Antioxidantes/química , alfa-Glucosidases/metabolismo
20.
Phytochemistry ; 190: 112859, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34218044

RESUMO

Thirty-one Vincan- and two Eburnan-type alkaloids were isolated from the aerial parts of Tabernaemontana bovina, whereas 20 of them are described the first time. Within the purified alkaloids, the firstly described taberbovcamine A features a 6/5/6/6/5 ring system. All the chemical structures were elucidated by employing extensive spectroscopic, computational electronic circular dichroism and X-ray diffraction methods. The two Eburnan-type alkaloids, 10,11-dimethoxy-16-O-methyllisoeburnamenine and 10,11-dimethoxy-isoeburnamenine were simultaneously identified by using the mentioned spectroscopic methods. Within the identified alkaloids, 10-hydroxy-14,15-didehydrovincanmine, 14,15-didehydrovincanmine, 14,15-didehydroapovincanmine, and criocerine increased the glucose consumption in a L6 myotube model.


Assuntos
Alcaloides , Tabernaemontana , Alcaloides/farmacologia , Hipoglicemiantes/farmacologia , Alcaloides Indólicos , Estrutura Molecular
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