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1.
J Cell Mol Med ; 28(16): e70032, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39175104

RESUMO

Breast cancer (BC) is one of the most common types of cancer among women worldwide. Lycorine (Lycoris radiata), a small molecule derived from the traditional Chinese herb Amaryllidaceae plants, has appeared potential effect on inhibiting the growth of cancer cells and inducing apoptosis in various types of cancer with minor side effects. To discuss the therapeutic effects and molecular mechanisms of lycorine on BC established by lycorine-treated S180 tumour-bearing mice in vivo. Furthermore, both the mitotic and microtubule assembly dynamics genes were performed by qPCR assays, and the protein expression associated with mitotic arrest was investigated by western blot. Lycorine was demonstrated to reduce sarcoma growth of S180 tumour-bearing mice and inhibit the proliferation of MCF-7 cells in concentration-dependent manner. Moreover, lycorine induced M phase cell cycle arrest via interfering with the mitotic apparatus regulated the expression of 20 genes and 15 proteins in cell cycle progression. Furthermore, this study confirmed that the potential effect of lycorine on BC might be mediated by cell cycle arrest in M phase for the first time. These results would be the consequence of exploitation of lycorine as a potential drug for BC therapy, however further preclinical and clinical studies are still needed.


Assuntos
Alcaloides de Amaryllidaceae , Neoplasias da Mama , Proliferação de Células , Lycoris , Fenantridinas , Fenantridinas/farmacologia , Alcaloides de Amaryllidaceae/farmacologia , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Animais , Lycoris/genética , Proliferação de Células/efeitos dos fármacos , Camundongos , Células MCF-7 , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Mitose/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral
2.
Nat Prod Rep ; 41(5): 721-747, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38131392

RESUMO

Covering: 2017 to 2023 (now)Amaryllidaceae alkaloids (AAs) are a unique class of specialized metabolites containing heterocyclic nitrogen bridging that play a distinct role in higher plants. Irrespective of their diverse structures, most AAs are biosynthesized via intramolecular oxidative coupling. The complex organization of biosynthetic pathways is constantly enlightened by new insights owing to the advancement of natural product chemistry, synthetic organic chemistry, biochemistry, systems and synthetic biology tools and applications. These promote novel compound identification, trace-level metabolite quantification, synthesis, and characterization of enzymes engaged in AA catalysis, enabling the recognition of biosynthetic pathways. A complete understanding of the pathway benefits biotechnological applications in the long run. This review emphasizes the structural diversity of the AA specialized metabolites involved in biogenesis although the process is not entirely defined yet. Moreover, this work underscores the pivotal role of synthetic and enantioselective studies in justifying biosynthetic conclusions. Their prospective candidacy as lead constituents for antiviral drug discovery has also been established. However, a complete understanding of the pathway requires further interdisciplinary efforts in which antiviral studies address the structure-activity relationship. This review presents current knowledge on the topic.


Assuntos
Alcaloides de Amaryllidaceae , Antivirais , Antivirais/farmacologia , Antivirais/química , Antivirais/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/metabolismo , Vias Biossintéticas , Estrutura Molecular , Relação Estrutura-Atividade
3.
Biochem Biophys Res Commun ; 730: 150393, 2024 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-39003865

RESUMO

Arboviruses such as chikungunya virus (CHIKV) and dengue virus (DENV) collectively afflict millions of individuals worldwide particularly in endemic countries like India, leading to substantial morbidity and mortality. With the lack of effective vaccines for both CHIKV and DENV in India, the search for antiviral compounds becomes paramount to control these viral infections. In line with this, our investigation was focused on screening natural compounds for their potential antiviral activity against CHIKV and DENV. Using different assays, including plaque assay, immunofluorescence, and reverse transcription-quantitative real-time PCR (qRT-PCR), out of 109 natural compounds tested, we confirmed lycorine's in vitro antiviral activity against CHIKV and DENV at low micromolar concentrations in different cell types. Time of addition assays indicated that lycorine does not impede viral entry. Additionally, qRT-PCR results along with time of addition assay suggested that lycorine interferes with the synthesis of negative strand viral RNA. Molecular docking analysis was done to understand the mode of inhibition of viral replication. The results revealed that the most likely binding site with the highest binding affinity of lycorine, was at the palm and finger domains, in the vicinity of the catalytic site of CHIKV and DENV RNA-dependent RNA polymerase (RdRp). Collectively, our data underscores the potential of lycorine to be developed as a direct acting inhibitor for DENV and CHIKV, addressing the critical need of requirement of an antiviral in regions where these viruses pose significant public health threats.


Assuntos
Alcaloides de Amaryllidaceae , Antivirais , Vírus Chikungunya , Vírus da Dengue , Fenantridinas , Replicação do RNA , RNA Viral , Animais , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Antivirais/farmacologia , Antivirais/química , Linhagem Celular , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/genética , Chlorocebus aethiops , Simulação por Computador , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/genética , Simulação de Acoplamento Molecular , Fenantridinas/farmacologia , Fenantridinas/química , Replicação do RNA/efeitos dos fármacos , RNA Viral/genética , RNA Viral/metabolismo
4.
New Phytol ; 241(5): 2258-2274, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38105545

RESUMO

Alkaloids are a large group of plant secondary metabolites with various structures and activities. It is important to understand their functions in the interplay between plants and the beneficial and pathogenic microbiota. Amaryllidaceae alkaloids (AAs) are unique secondary metabolites in Amaryllidaceae plants. Here, we studied the interplay between AAs and the bacteriome in Lycoris radiata, a traditional Chinese medicinal plant containing high amounts of AAs. The relationship between AAs and bacterial composition in different tissues of L. radiata was studied. In vitro experiments revealed that AAs have varying levels of antimicrobial activity against endophytic bacteria and pathogenic fungi, indicating the importance of AA synthesis in maintaining a balance between plants and beneficial/pathogenic microbiota. Using bacterial synthetic communities with different compositions, we observed a positive feedback loop between bacteria insensitive to AAs and their ability to increase accumulation of AAs in L. radiata, especially in leaves. This may allow insensitive bacteria to outcompete sensitive ones for plant resources. Moreover, the accumulation of AAs enhanced by insensitive bacteria could benefit plants when challenged with fungal pathogens. This study highlights the functions of alkaloids in plant-microbe interactions, opening new avenues for designing plant microbiomes that could contribute to sustainable agriculture.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Lycoris , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/metabolismo , Lycoris/química , Lycoris/metabolismo , Alcaloides/metabolismo , Extratos Vegetais/química
5.
Toxicol Appl Pharmacol ; 489: 117017, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38925513

RESUMO

Liver fibrosis, a progressive process of fibrous scarring, results from the accumulation of extracellular matrix proteins (ECM). If left untreated, it often progresses to diseases such as cirrhosis and hepatocellular carcinoma. Lycorine, a natural alkaloid derived from medicinal plants, has shown diverse bioactivities by targeting JAK2/STAT3 signaling, but its pharmacological effects and potential molecular mechanisms in liver fibrosis remains largely unexplored. The purpose of this study is to elucidate the pharmacological activity and molecular mechanism of lycorine in anti-hepatic fibrosis. Findings indicate that lycorine significantly inhibited hepatic stellate cells (HSCs) activation by reducing the expression of α-SMA and collagen-1. In vivo, lycorine treatment alleviated carbon tetrachloride (CCl4) -induced mice liver fibrosis, improving liver function, decreasing ECM deposition, and inhibiting fibrosis-related markers' expression. Mechanistically, it was found that lycorine exerts protective activity through the JAK2/STAT3 and PI3K/AKT signaling pathways, as evidenced by transcriptome sequencing technology and small molecule inhibitors. These results underscore lycorine's potential as a therapeutic drug for liver fibrosis.


Assuntos
Alcaloides de Amaryllidaceae , Tetracloreto de Carbono , Células Estreladas do Fígado , Janus Quinase 2 , Cirrose Hepática , Fenantridinas , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Tetracloreto de Carbono/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Masculino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Fenantridinas/farmacologia , Fenantridinas/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Linhagem Celular
6.
J Nat Prod ; 87(9): 2317-2326, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39229678

RESUMO

This phytochemical study presents the isolation of eight alkaloids from Zephyranthes citrina Baker. The structures of the new alkaloids, zephycitrine (1) and 6-oxonarcissidine (2), were established by analysis of spectroscopic and spectrometric data. Processing the EtOH extract under acid-base conditions yielded the unreported isolation artifacts 3 and 4. This work also provides analytical data for alkaloids not properly described in the literature (5 and 6). The hippeastidine/zephyranine scaffolds in derivatives 3, 4, and 8-10 are also thoroughly discussed. Furthermore, a cytotoxicity screening of 25 Amaryllidaceae alkaloids isolated from Z. citrina was performed. Only the known alkaloids haemanthamine (12), haemanthidine (13), and lycorine (27) showed significant cell growth inhibition.


Assuntos
Alcaloides de Amaryllidaceae , Amaryllidaceae , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Amaryllidaceae/química , Humanos , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Fenantridinas/farmacologia , Fenantridinas/química
7.
Planta Med ; 90(12): 900-937, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39029914

RESUMO

There is considerable interest in the utilisation of plants against inflammation. Over 50 species of the plant family Amaryllidaceae are known for such usage in traditional medicine. This review was undertaken to identify the chemical principles responsible for these anti-inflammatory effects. It describes the findings from in vitro, in vivo and in silico studies, as well as the probes made on the mechanisms of action. The literature search returned over 600 hits, of which around 130 were chosen for their relevance to the text. Over 140 compounds have thus far been screened for anti-inflammatory effects. These were mostly isoquinoline alkaloids but also included other classes of secondary metabolites such as chromones, flavonoids and triterpenoids. In vitro studies were carried out in mononuclear cells such as lymphocytes, monocytes, neutrophils and macrophages, against which no serious side effects were observed. The constituents were also effective against inflammation induced by physical and chemical stimuli in a variety of murine test subjects. Chief among the compounds were the isoquinoline alkaloids lycorine and narciclasine, which displayed potent effects against pain, swelling, asthma and arthritis, amongst others. From a mechanistic perspective, several of the compounds were shown to mediate in inflammatory pathways, notably via the modulation of both pro-inflammatory (such as NF-κB, TNF-α and IL-1) and anti-inflammatory (such as IL-10 and TGF-ß) factors. Useful insights also emerged from active-site docking studies of some of the compounds. The Amaryllidaceae affords a rich and diverse platform for the discovery of potential anti-inflammatory drugs.


Assuntos
Alcaloides de Amaryllidaceae , Amaryllidaceae , Anti-Inflamatórios , Inflamação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Animais , Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Inflamação/tratamento farmacológico , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Fenantridinas/farmacologia , Fenantridinas/química
8.
Chem Biodivers ; 21(3): e202302122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38354224

RESUMO

Griffinia gardneriana Ravenna, Griffinia liboniana Morren and Griffinia nocturna Ravenna (Amarillydaceae) are bulbous plants found in tropical regions of Brazil. Our work aimed to determine the alkaloid profiles of Griffinia spp. and evaluate their anxiolytic potential through in vivo and in silico assays. The plants grown in greenhouses were dried and their ground bulbs were subjected to liquid-liquid partitions, resulting in alkaloid fractions that were analyzed by gas chromatography coupled to mass spectrometry (GC-MS). Anxiolytic activity was evaluated in zebrafish (Danio rerio) through intraperitoneal injection at doses of 40, 100 and 200 mg/kg in light-dark box test. GC-MS analyses revealed 23 alkaloids belonging to different skeleton types: lycorine, homolychorine, galanthamine, crinine, haemanthamine, montanine and narcisclasine. The chemical profiles were relatively similar, presenting 8 alkaloids common to the three species. The major component for G. gardneriana and G. liboniana was lycorine, while G. nocturna consisted mainly of anhydrolycorine. All three alkaloid fractions demonstrated anxiolytic effect. Furthermore, pre-treatment with diazepam and pizotifen drugs was able to reverse the anxiolytic action, indicating involving the GABAergic and serotonergic receptors. Molecular docking showed that the compounds vittatine, lycorine and 11,12-dehydro-2-methoxyassoanine had high affinity with both receptors, suggesting them to be responsible for the anxiolytic effect.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Ansiolíticos , Fenantridinas , Animais , Amaryllidaceae/química , Peixe-Zebra , Ansiolíticos/farmacologia , Simulação de Acoplamento Molecular , Cromatografia Gasosa-Espectrometria de Massas/métodos , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química
9.
Int J Mol Sci ; 24(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36768386

RESUMO

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2-32) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1-32 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors.


Assuntos
Adenocarcinoma , Alcaloides de Amaryllidaceae , Antineoplásicos , Neoplasias do Colo , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Adenocarcinoma/tratamento farmacológico , Carbamatos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Colo/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Antineoplásicos/química , Doxorrubicina/farmacologia , Linhagem Celular Tumoral
10.
Molecules ; 28(7)2023 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-37049986

RESUMO

The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although Hymenocallis littoralis has been studied for decades, its polar components were rarely explored. The current phytochemical investigation of Amaryllidaceae alkaloids from H. littoralis led to the identification of three previously undescribed compounds: O-demethyl-norlycoramine (1), (-)-2-epi-pseudolycorine (2) and (+)-2-epi-pseudolycorine (3), together with eight known compounds: 6α-hydroxyhippeastidine (4), 6ß-hydroxyhippeastidine (5), lycorine (6), 2-epi-lycorine (7), zephyranthine (8), ungeremine (9), pancratistatin (10) and 9-O-demethyl-7-O-methyllycorenine (11). Among the eight previously reported compounds, five were isolated from H. littoralis for the first time (compounds 4, 5, 7, 8, and 9). Compounds 1, 4, 5, 7, 8, and 11 exhibited weak anti-SARS-CoV-2 activity (EC50 = 40-77 µM) at non-cytotoxic concentrations. Assessment of cytotoxicity on the Vero-E6 cell line revealed lycorine and pancratistatin as cytotoxic substances with CC50 values of 1.2 µM and 0.13 µM, respectively. The preliminary structure-activity relationship for the lycorine-type alkaloids in this study was further investigated, and as a result ring C appears to play a crucial role in their anti-SARS-CoV-2 activity.


Assuntos
Alcaloides de Amaryllidaceae , Amaryllidaceae , COVID-19 , Liliaceae , Alcaloides de Amaryllidaceae/farmacologia , Alcaloides de Amaryllidaceae/química , Amaryllidaceae/química
11.
Molecules ; 28(14)2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37513280

RESUMO

The genus Clinanthus Herb. is found in the Andes Region (South America), mainly in Peru, Ecuador, and Bolivia. These plants belong to the Amaryllidaceae family, specifically the Amaryllidoideae subfamily, which presents an exclusive group of alkaloids known as Amaryllidaceae alkaloids that show important structural diversity and pharmacological properties. It is possible to find some publications in the literature regarding the botanical aspects of Clinanthus species, although there is little information available about their chemical and biological activities. The aim of this work was to obtain the alkaloid profile and the anti-cholinesterase activity of four different samples of Clinanthus collected in South America: Clinanthus sp., Clinanthus incarnatus, and Clinanthus variegatus. The alkaloid extract of each sample was analyzed by gas chromatography coupled with mass spectrometry (GC-MS), and their potential against the enzymes acetyl- and butyrylcholinesterase were evaluated. Thirteen alkaloids have been identified among these species, while six unidentified structures have also been detected in these plants. The alkaloid extract of the C. variegatus samples showed the highest structural diversity as well as the best activity against AChE, which was likely due to the presence of the alkaloid sanguinine. The results suggest this genus as a possible interesting new source of Amaryllidaceae alkaloids, which could contribute to the development of new medicines.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Alcaloides de Amaryllidaceae/farmacologia , Butirilcolinesterase/química , Amaryllidaceae/química , Alcaloides/química , Inibidores da Colinesterase/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , América do Sul
12.
Molecules ; 28(6)2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36985571

RESUMO

Cancer is a major cause of death and an impediment to increasing life expectancy worldwide. With the aim of finding new molecules for chemotherapeutic treatment of epidemiological relevance, ten alkaloid fractions from Amaryllidaceae species were tested against six cancer cell lines (AGS, BT-549, HEC-1B, MCF-7, MDA-MB 231, and PC3) with HaCat as a control cell line. Some species determined as critically endangered with minimal availability were propagated using in vitro plant tissue culture techniques. Molecular docking studies were carried out to illustrate binding orientations of the 30 Amaryllidaceae alkaloids identified in the active site of some molecular targets involved with anti-cancer activity for potential anti-cancer drugs. In gastric cancer cell line AGS, the best results (lower cell viability percentages) were obtained for Crinum jagus (48.06 ± 3.35%) and Eucharis bonplandii (45.79 ± 3.05%) at 30 µg/mL. The research focused on evaluating the identified alkaloids on the Bcl-2 protein family (Mcl-1 and Bcl-xL) and HK2, where the in vitro, in silico and statistical results suggest that powelline and buphanidrine alkaloids could present cytotoxic activity. Finally, combining experimental and theoretical assays allowed us to identify and characterize potentially useful alkaloids for cancer treatment.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Antineoplásicos , Neoplasias , Extratos Vegetais/farmacologia , Amaryllidaceae/química , Simulação de Acoplamento Molecular , Alcaloides/química , Alcaloides de Amaryllidaceae/farmacologia
13.
Molecules ; 28(3)2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36770905

RESUMO

Amaryllidaceae alkaloids are secondary metabolites with interesting medicinal properties. Almost every Narcissus species can synthesize them and constitute an excellent source for their isolation and study. Several Amaryllidaceae alkaloids have shown acetylcholinesterase inhibitory activities and are a promising tool for treating cholinergic disorders such as Alzheimer's disease (AD). Indeed, three of the four palliative treatments approved for AD are acetylcholinesterase (AChE) inhibitors and one of them, galanthamine, is an Amaryllidaceae alkaloid itself. This molecule is currently isolated from natural sources. However, its production is insufficient to supply the increasing demand for the active principle. Our main aim is to discover tools to improve galanthamine production and to prospect for potential new and more efficient drugs for AD treatment. Furthermore, we seek to broaden the knowledge of plants of the genus Narcissus from a chemotaxonomic perspective. Hence, in this study, we evaluate the alkaloid content through GC-MS and the AChE inhibitory activity of ten autumn-flowering Narcissus, which have been less studied than their spring-flowering counterparts. A total of thirty Amaryllidaceae alkaloids have been found, twenty-eight properly identified. Two Narcissus contained galanthamine, and seven were able to inhibit AChE.


Assuntos
Alcaloides de Amaryllidaceae , Amaryllidaceae , Narcissus , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Inibidores da Colinesterase , Galantamina/farmacologia , Narcissus/química
14.
J Appl Biomed ; 21(1): 36-47, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37016777

RESUMO

Skin cancer has high rates of mortality and therapeutic failure. In this study, to develop a multi-agent strategy for skin cancer management, the selective cytotoxicity of several alkaloid fractions and pure alkaloids isolated from Amaryllidaceae species was evaluated in melanoma cells. In addition, UVB-stimulated keratinocytes (HaCaT) were exposed to seven alkaloid fractions characterized by GC-MS, and the production of intracellular reactive oxygen species (ROS) and IL-6, were measured to evaluate their photoprotection effects. The Eucharis caucana (bulb) alkaloid fraction (20 µg/ml) had a clear effect on the viability of melanoma cells, reducing it by 45.7% without affecting healthy keratinocytes. This alkaloid fraction and tazettine (both at 2.5 µg/ml) suppressed UVB-induced ROS production by 31.6% and 29.4%, respectively. The highest anti-inflammatory potential was shown by the Zephyranthes carinata (bulb) alkaloid fraction (10 µg/ml), which reduced IL-6 production by 90.8%. According to the chemometric analysis, lycoramine and tazettine had a photoprotective effect on the UVB-exposed HaCaT cells, attenuating the production of ROS and IL-6. These results suggest that Amaryllidaceae alkaloids have photoprotective and therapeutic potential in skin cancer management, especially at low concentrations.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Melanoma , Neoplasias Cutâneas , Humanos , Alcaloides de Amaryllidaceae/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Interleucina-6 , Alcaloides/farmacologia , Queratinócitos , Neoplasias Cutâneas/tratamento farmacológico , Melanoma/tratamento farmacológico
15.
Mol Pharm ; 19(6): 1839-1852, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35559658

RESUMO

Pancratistatin (PST) is a natural antiviral alkaloid that has demonstrated specificity toward cancerous cells and explicitly targets the mitochondria. PST initiates apoptosis while leaving healthy, noncancerous cells unscathed. However, the manner by which PST induces apoptosis remains elusive and impedes the advancement of PST as a natural anticancer therapeutic agent. Herein, we use neutron spin-echo (NSE) spectroscopy, molecular dynamics (MD) simulations, and supporting small angle scattering techniques to study PST's effect on membrane dynamics using biologically representative model membranes. Our data suggests that PST stiffens the inner mitochondrial membrane (IMM) by being preferentially associated with cardiolipin, which would lead to the relocation and release of cytochrome c. Second, PST has an ordering effect on the lipids and disrupts their distribution within the IMM, which would interfere with the maintenance and functionality of the active forms of proteins in the electron transport chain. These previously unreported findings implicate PST's effect on mitochondrial apoptosis.


Assuntos
Alcaloides de Amaryllidaceae , Antineoplásicos , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Antineoplásicos/química , Apoptose , Isoquinolinas/química , Isoquinolinas/farmacologia , Mitocôndrias
16.
Pharmacol Res ; 175: 105985, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863821

RESUMO

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus and no effective therapy is approved. Here, lycorine, a natural alkaloid, was identified as a potential drug for DPN by the bioinformatics analysis of GEO datasets and Connectivity Map database. Lycorine administration improved peripheral nerve function and autophagy-associated proteins of diabetic mice. Again, in vitro high glucose-cultured rat Schwann cells (RSC96) showed enhanced autophagosome marker LC3-II with the treatment of lycorine. Additionally, beclin-1 and Atg3 were decreased in high glucose-stimulated RSC96 cells, which were reversed by lycorine treatment. Furthermore, DPN-associated differentially expressed genes (DEGs) from GEO datasets and lycorine-drug targets from PubChem and PharmMapper were visually analyzed and revealed that MMP9 was both DPN-associated DEGs and lycorine-drug target. Functional enrichment analysis of MMP9-relevant genes showed that cell energy metabolism was involved. Moreover, lycorine reduced high glucose-enhanced MMP9 expression in RSC96 cells. Overexpression of MMP9 attenuated lycorine-induced the expression of beclin-1, Atg3 and LC3-II in high glucose-cultured RSC96 cells. In addition, AMPK pathway activation was confirmed in lycorine-treated high glucose-cultured RSC96 cells. Then AMPK pathway inhibition attenuated lycorine-reduced MMP9 expression in high glucose-treated RSC96 cells. Molecular docking analysis revealed that lycorine bound the domain of AMPK containing Thr 172 site, which affected AMPK (Thr 172) phosphorylation. Finally, AMPK pathway activation and MMP9 downregulation were also revealed in the sciatic nerves of diabetic mice administrated with lycorine. Taken together, lycorine was advised to promote Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation-induced LC3-II transformation in diabetic peripheral neuropathy.


Assuntos
Alcaloides de Amaryllidaceae/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fenantridinas/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Alcaloides de Amaryllidaceae/farmacologia , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fenantridinas/farmacologia , Ratos , Células de Schwann/efeitos dos fármacos , Nervo Isquiático/fisiologia , Transdução de Sinais/efeitos dos fármacos
17.
Org Biomol Chem ; 20(19): 3960-3966, 2022 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-35471452

RESUMO

Polycyclic compounds with N-methyl substitution, structurally related to Amaryllidaceae alkaloids, have been synthesised, together with their analogues bearing a quaternary nitrogen atom. To prevent the lone electron pair of the nitrogen from interfering with the reaction sequence, two approaches to the synthesis were investigated: N-oxidation and Boc protection of the nitrogen. The second method was more successful due to the limited stability of N-oxides in the halocyclisation step. An asymmetric version of the synthesis was also developed for this type of compounds. The prepared products were tested in vitro for their cholinesterase inhibitory activity and the results were rationalised by molecular docking studies with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). In general, our products were more active against BuChE than against AChE, and it was noted that larger ligands should be prepared for future studies, since in some cases acetylcholine can still fit into the active site along with the bound ligand.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Acetilcolinesterase/metabolismo , Alcaloides/química , Amaryllidaceae/química , Amaryllidaceae/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Humanos , Simulação de Acoplamento Molecular , Nitrogênio , Relação Estrutura-Atividade
18.
Molecules ; 27(12)2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35744934

RESUMO

A 15-step chemoenzymatic total synthesis of C-1 methoxycarbonyl narciclasine (10) was accomplished. The synthesis began with the toluene dioxygenase-mediated dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiol (12) as a single enantiomer. Further key steps included a nitroso Diels-Alder reaction and an intramolecular Heck cyclization. The C-1 homolog 10 was tested and evaluated for antiproliferative activity against natural narciclasine (1) as the positive control. Experimental and spectral data are reported for all novel compounds.


Assuntos
Alcaloides de Amaryllidaceae , Alcaloides de Amaryllidaceae/farmacologia , Ciclização , Estrutura Molecular , Fenantridinas/farmacologia , Estereoisomerismo
19.
Molecules ; 27(14)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35889346

RESUMO

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer's disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.


Assuntos
Allium , Alcaloides de Amaryllidaceae , Amaryllidaceae , Crinum , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Crinum/química , Humanos , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia
20.
Molecules ; 27(9)2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35566325

RESUMO

Candida species are the main fungal agents causing infectious conditions in hospital patients. The development of new drugs with antifungal potential, increased efficacy, and reduced toxicity is essential to face the challenge of fungal resistance to standard treatments. The aim of this study is to evaluate the in vitro antifungal effects of two crude extracts of Crinum americanum L., a rich alkaloid fraction and lycorine alkaloid, on the Candida species. As such, we used a disk diffusion susceptibility test, determined the minimum inhibitory concentration (MIC), and characterized the components of the extracts using Electrospray Ionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (ESI FT-ICR MS). The extracts were found to have antifungal activity against various Candida species. The chemical characterization of the extracts indicated the presence of alkaloids such as lycorine and crinine. The Amaryllidaceae family has a promising antifungal potential. Furthermore, it was found that the alkaloid lycorine directly contributes to the effects that were observed for the extracts and fraction of C. americanum.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Crinum , Alcaloides/química , Alcaloides/farmacologia , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Candida , Crinum/química , Humanos , Fenantridinas , Extratos Vegetais/química , Extratos Vegetais/farmacologia
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