Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 212
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Org Chem ; 87(15): 9565-9575, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35834751

RESUMO

A naturally occurring alkaloid aloperine was utilized as a chiral skeleton for the development of new ligands/catalysts in asymmetric synthesis. A number of N-substituted aloperines have been prepared, and a Pd-catalyzed asymmetric hydroarylation of ketimines using these chiral 1,3-diamine ligands was reported. A range of chiral sulfonyl amides were prepared in high yields and enantioselectivities. The stereoselectivity and structure relationships of aloperines have been studied. In addition, preliminary studies on the desymmetrization of meso-anhydride have also shown that these diamines have good potential in organocatalysis. These discoveries would provide a new future development for natural product-inspired chiral ligand design and developments.


Assuntos
Produtos Biológicos , Paládio , Diaminas/química , Iminas , Ligantes , Nitrilas , Quinolizidinas , Estereoisomerismo
2.
Molecules ; 27(13)2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35807242

RESUMO

Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) is a Mediterranean plant introduced to South America and other regions for ornamental purposes. However, it is considered an invasive shrub due to its reproductive vigor in many areas. Unlike other Genista plants, G. monspessulana has few studies disclosing its biologically active components, particularly cytotoxic agents against cancer cells. Thus, as part of our research on anti-proliferative bioactives, a set of ethanolic seed extracts from ten accessions of G. monspessulana, collected in the Bogotá plateau, were evaluated against four cell lines: PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), A549 (lung carcinoma), and L929 (normal mouse fibroblasts). Extracts were also analyzed through liquid chromatography coupled with mass spectrometry (LC/MS) to record chemical fingerprints and determine the composition and metabolite variability between accessions. Using multiple covariate statistics, chemical and bioactivity datasets were integrated to recognize patterns and identify bioactive compounds among studied extracts. G. monspessulana seed-derived extracts exhibited dose-dependent antiproliferative activity on PC-3 and SiHa cell lines (>500 µg/mL < IC50 < 26.3 µg/mL). Seven compounds (1-7) were inferred as the compounds most likely responsible for the observed anti-proliferative activity and subsequently isolated and identified by spectroscopic techniques. A tricyclic quinolizidine (1) and a pyranoisoflavone (2) were found to be the most active compounds, exhibiting selectivity against PC-3 cell lines (IC50 < 18.6 µM). These compounds were used as precursors to obtain a quinolizidine-pyranoisoflavone adduct via Betti reaction, improving the activity against PC-3 and comparable to curcumin as the positive control. Results indicated that this composition-activity associative approach is advantageous to finding those bioactive principles efficiently within active extracts. This correlative association can be employed in further studies focused on the targeted isolation of anti-proliferative compounds from Genista plants and accessions.


Assuntos
Carcinoma , Genista , Quinolizidinas , Animais , Genista/química , Masculino , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sementes
3.
J Agric Food Chem ; 70(29): 9214-9226, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35849433

RESUMO

As part of our ongoing investigation of pesticide active quinolizidine alkaloids (QAs) from the family Fabaceae, the chemical constituents of the seeds of Thermopsis lanceolata R. Br. were systematically investigated. Bioassay-guided fractionation and purification of the crude extract led to the isolation of seventeen new QAs (1-17), including three new naturally occurring compounds (15-17), along with 15 known compounds (18-32). Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HRESIMS) and quantum chemistry calculations (13C NMR and ECD). The antitomato spotted wilt virus activities and insecticidal activities against Aphis fabae, Nilaparvata lugens (Stal), and Tetranychus urticae of compounds 1-32 were screened using the lesion counting method, spray method, and rice-stem dipping method, respectively. Biological tests indicated that compounds 6, 9, 10, and 18 displayed significant anti-TSWV activities compared with the positive control ningnanmycin. Compounds 3, 4, and 5 showed better insecticidal activities against A. fabae with LC50 values of 10.07, 12.07, and 6.56 mg/L, respectively. Moreover, compounds 5, 18, and 24 exhibited moderate insecticidal activities against N. lugens (Stal) with LC50 values of 37.91, 53.44, and 31.21 mg/L, respectively. Furthermore, compounds 9 and 10 exhibited moderate insecticidal activities against T. urticae.


Assuntos
Alcaloides , Afídeos , Fabaceae , Inseticidas , Quinolizidinas , Alcaloides/análise , Alcaloides/farmacologia , Animais , Inseticidas/química , Quinolizidinas/farmacologia , Sementes/química
4.
J Org Chem ; 87(14): 8871-8883, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35759553

RESUMO

A Ni-catalyzed (4 + 2) cycloaddition of bicyclic 3-azetidinones and alkynes was developed to access indolizidine and quinolizidine alkaloids. A key element was the development of a diazomethylation procedure that allows the efficient synthesis of bicyclic azetidinones from pyroglutamic and 6-oxopiperidine-2-carboxylic acid. A ligand screening led to improved regioselectivity and enantiopurity during the Ni-catalyzed (4 + 2) cycloaddition. This straightforward methodology was leveraged to synthesize (+)-ipalbidine, (+)-septicine, (+)-seco-antofine, and (+)-7-methoxy-julandine.


Assuntos
Alcaloides , Indolizidinas , Quinolizidinas , Catálise , Reação de Cicloadição , Níquel
5.
Molecules ; 27(9)2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35566183

RESUMO

Lupinus plants are well-recognized due to their significant alkaloid content, which has made them the subject of several studies. However, the lack of chemical and biological information on the Colombian Lupinus species remains a fact. Therefore, the alkaloidal fractions from the leaves of L. mirabilis obtained by conventional solvent and ultrasound-assisted extraction (CSE and UAE, respectively) at different time frames were analyzed. Sparteine (2) was the main component in all cases; however, its relative abundance showed large variability, ranging from 64.7% to 80.6%. Minor constituents were also affected by the extraction conditions. In general, prolonged times gave a higher proportion of alkaloids under CSE, while only a slight decrease was observed under UAE. Both the method and extraction time appeared to equally affect the ratios of particular alkaloids, leading to variations in their effect on the mycelial growth of Fusarium oxysporum. Holistic analysis through multiple-covariate statistical methods as an approach to integrating chemical and bioactivity datasets allowed inferring the compounds most likely responsible for the changes in mycelial growth inhibition. 13α-Hydroxylupanine (12) might represent a promising compound to be included in further studies against this phytopathogen.


Assuntos
Alcaloides , Lupinus , Mirabilis , Quinolizidinas , Alcaloides/química , Antifúngicos/análise , Antifúngicos/farmacologia , Lupinus/química , Folhas de Planta/química , Quinolizidinas/química
6.
Phytomedicine ; 100: 154074, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35397283

RESUMO

RATIONALE: Alveolar epithelial cell death, inflammation, and oxidative stress are typical features of acute lung injury (ALI). Aloperine (Alo), an alkaloid isolated from Sophora alopecuroides, has been reported to display various biological effects, such as anti-inflammatory, immunoregulatory, and anti-oxidant properties. In this study, we investigated the effects and mechanisms of Alo in treating a lipopolysaccharide (LPS)-induced ALI in a murine model. METHODS: The effects of Alo in LPS-induced ALI were investigated in C57BL/6 mice. The RIPK1 inhibitor (Nec-1) and the RIPK3 inhibitor (GSK'872) were used to evaluate the relationship of necroptosis, NF-κB activation, and PDC subunits in LPS-treated mouse alveolar epithelial cells (MLE-12). Then the effects of Alo on necroptosis, inflammation, and oxidative stress of LPS-stimulated MLE-12 cells were evaluated. RESULTS: Alo significantly attenuated histopathological lung injuries and reduced lung wet/dry ratio in LPS-induced ALI mice. Alo also remarkedly reduced total protein and neutrophils recruitment in bronchoalveolar lavage fluid of ALI mice. Meanwhile, Alo ameliorated the LPS-induced necroptosis in the lungs of ALI mice. The RIPK3 inhibitor GSK'872, but not the RIPK1 inhibitor Nec-1, reversed LPS-induced p65 phosphorylation and translocation to the nucleus in MLE-12 cells. GSK'872 also reversed the LPS-induced increase in ROS and binding of RIPK3 and PDC subunits in MLE-12 cells. Moreover, Alo down-regulated the levels of p-RIPK1, p-RIPK3, p-MLKL, p-p65, the translocation of p65 to the nucleus, and reduced the expression of IL-6 and IL-8 in LPS-stimulated MLE-12 cells. Alo also inhibited the binding of RIPK3 and PDC-E1α, PDC-E1ß, PDC-E2, and PDC-E3 and the ROS production in LPS-treated MLE-12 cells. CONCLUSION: The present study validated the beneficial effects of Alo on LPS-induced ALI , suggesting Alo may be a new drug candidate against ALI.


Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Animais , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Necroptose , Estresse Oxidativo , Piperidinas/farmacologia , Quinolizidinas , Espécies Reativas de Oxigênio
7.
Sci Total Environ ; 834: 155283, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35439507

RESUMO

Phytotoxins are produced in plants including agricultural crops. Lupins and other plants of the Fabaceae family produce toxic alkaloids. These alkaloids have been studied in food and feed, however, the environmental fate of alkaloids produced by cultivated lupins is largely unknown. Therefore, we conducted an agricultural field experiment to investigate the occurrence of indole and quinolizidine alkaloids in lupin plant tissues, soil, soil pore water and in drainage water. During the field experiment, alkaloids were regularly quantified (median concentrations) in lupin (13-8.7 × 103 ng/g dry weight (dw)), and topsoils at depth 0-5 cm (0.1-10 ng/g dw), and depth 15-30 cm (0.2-8.5 ng/g dw), soil pore water (0.2-7.5 ng/L) and drainage water samples (0.4-18 ng/L). Lupanine was the dominant alkaloid in all collected samples. Cumulative amounts of alkaloids emitted via drainage water were around 0.1-11 mg/ha for individual alkaloids over one growing season. The total cumulative amount of alkaloid in drainage water was 14 mg/ha, which is a very small amount compared to the mass of alkaloid in the lupin biomass (11 kg/ha) and soil (0.02 kg/ha). Nearly half of the alkaloids were exported in the drainage water during high flow events, indicating that alkaloids transport preferentially via macropores. These findings indicate that drainage from lupin cultivated areas contribute to surface water contamination. The environmental and ecotoxicological relevance of alkaloids as newly identified aquatic micropollutants in areas with agricultural activities have yet to be assessed.


Assuntos
Alcaloides , Lupinus , Quinolizidinas , Indóis , Solo , Água
8.
Nat Prod Rep ; 39(7): 1423-1437, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35302146

RESUMO

Covering: up to 2022Quinolizidine alkaloids (QAs) are a class of alkaloids that accumulate in a variety of leguminous plants and have applications in the agricultural, pharmaceutical and chemical industries. QAs are notoriously present in cultivated lupins (Lupinus spp.) where they complicate the use of the valuable, high-protein beans due to their toxic properties and bitter taste. Compared to many other alkaloid classes, the biosynthesis of QAs is poorly understood, with only the two first pathway enzymes having been discovered so far. In this article, we review the different biosynthetic hypotheses that have been put forth in the literature (1988-2009) and highlight one particular hypothesis (1988) that agrees with the often ignored precursor feeding studies (1964-1994). Our focus is on the biosynthesis of the simple tetracyclic QA (-)-sparteine, from which many of the QAs found in lupins derive. We examine every pathway step on the way to (-)-sparteine and discuss plausible mechanisms, altogether proposing the involvement of 6-9 enzymes. Together with the new resources for gene discovery developed for lupins in the past few years, this review will contribute to the full elucidation of the QA pathway, including the identification and characterization of the missing pathway enzymes.


Assuntos
Alcaloides , Lupinus , Quinolizidinas , Esparteína , Lupinus/química , Lupinus/genética , Lupinus/metabolismo , Plantas/metabolismo , Esparteína/metabolismo
9.
Molecules ; 27(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35011535

RESUMO

Fusarium oxysporum is an aggressive phytopathogen that affects various plant species, resulting in extensive local and global economic losses. Therefore, the search for competent alternatives is a constant pursuit. Quinolizidine alkaloids (QA) are naturally occurring compounds with diverse biological activities. The structural diversity of quinolizidines is mainly contributed by species of the family Fabaceae, particularly the genus Lupinus. This quinolizidine-based chemo diversity can be explored to find antifungals and even mixtures to address concomitant effects on F. oxysporum. Thus, the antifungal activity of quinolizidine-rich extracts (QREs) from the leaves of eight greenhouse-propagated Lupinus species was evaluated to outline promising QA mixtures against F. oxysporum. Thirteen main compounds were identified and quantified using an external standard. Quantitative analysis revealed different contents per quinolizidine depending on the Lupinus plant, ranging from 0.003 to 32.8 mg/g fresh leaves. Bioautography showed that all extracts were active at the maximum concentration (5 µg/µL). They also exhibited >50% mycelium growth inhibition. All QREs were fungistatic except for the fungicidal QRE of L. polyphyllus Lindl. Angustifoline, matrine, 13α-hydroxylupanine, and 17-oxolupanine were ranked to act jointly against the phytopathogen. Our findings constitute reference information to better understand the antifungal activity of naturally afforded QA mixtures from these globally important plants.


Assuntos
Antifúngicos/farmacologia , Lupinus/química , Extratos Vegetais/farmacologia , Quinolizidinas/farmacologia , Antifúngicos/química , Cromatografia Gasosa-Espectrometria de Massas , Efeito Estufa , Lupinus/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Quinolizidinas/química
10.
Tissue Cell ; 74: 101706, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34883316

RESUMO

Anti-tumorous effect of Aloperine (ALO) has been previously found. This study examined the role and the underlying mechanism of ALO in colorectal cancer (CRC). CRC cells were processed by different concentrations of ALO, and subsequently the cell proliferation was detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and miR-296-5p expression was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the target gene of miR-296-5p was predicted by TargetScan and confirmed by dual-luciferase reporter assay. The expressions of signal transducer and activator of transcription 3 (STAT3), apoptosis-related proteins and epithelial-mesenchymal transition (EMT)-related markers were measured by Western blot. Clone formation assay, flow cytometry, wound-healing and Transwell assays were respectively employed to detect cell proliferation, apoptosis, migration and invasion. ALO inhibited CRC cell proliferation in a dose-dependent manner. MiR-296-5p was low-expressed in CRC tissues and cells, and ALO promoted miR-296-5p expression. STAT3 was targeted by miR-296-5p. Up-regulation of miR-296-5p and ALO treatment both suppressed STAT3 expression, inhibited CRC cell proliferation, migration, invasion as well as the expressions of Bcl-2 and N-cadherin, but promoted apoptosis and expressions of Bax and E-cadherin, which were all reversed by overexpressed STAT3. ALO inhibited CRC cell proliferation, metastasis and EMT but promoted apoptosis via regulating miR-296-5p/STAT3 axis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Quinolizidinas/farmacologia , RNA Neoplásico/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HCT116 , Células HT29 , Humanos , MicroRNAs/genética , Metástase Neoplásica , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Fator de Transcrição STAT3/genética
11.
J Recept Signal Transduct Res ; 42(1): 88-94, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33256538

RESUMO

Age-related macular degeneration (AMD) is a complex multifactorial disease associated with the dysfunction of retinal pigment epithelium (RPE). Aloperine is a quinolizidine alkaloid that has been proven to possess broad pharmacological activities. However, the effects of aloperine on AMD remain unclear. In the present study, we used hydrogen peroxide (H2O2) to induce oxidative injury in human RPE cells (ARPE-19 cells). ARPE-19 cells were pretreated with different concentrations of aloperine for 2 h, followed by H2O2 exposure. Cell cytotoxicity was determined using lactate dehydrogenase (LDH) release assay. Cell viability was measured using Cell Counting Kit-8 (CCK-8) assay. The reactive oxygen species (ROS) generation, malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-PX) activity were detected to reflect oxidative status. Western blot was performed to detect the expressions of bcl-2, bax, nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). The activity of caspase-3 was also assessed to indicate cell apoptosis. In addition, ARPE-19 cells were transfected with siNrf2 to knock down Nrf2. Our results showed that pretreatment with aloperine elevated the reduced cell viability of H2O2-induced ARPE-19 cells in a dose-dependent manner. Aloperine greatly decreased the production of ROS and MDA, and increased the activities of SOD and GSH-PX in H2O2-stimulated ARPE-19 cells. H2O2-caused a decrease in bcl-2 expression and increases in bax expression and caspase-3 activity were mitigated by aloperine. Moreover, aloperine treatment enhanced the expression levels of Nrf2 in nuclear fraction and the HO-1 expression in lysates. Knockdown of Nrf2 reversed the protective effects of aloperine on H2O2-induced ARPE-19 cells. In conclusion, these findings demonstrated that aloperine protected ARPE-19 cells from H2O2-induced oxidative stress and apoptosis in part via activating the Nrf2/HO-1 signaling pathway. The findings suggested a therapeutic potential of aloperine for the treatment of ADM.


Assuntos
Peróxido de Hidrogênio , Fator 2 Relacionado a NF-E2 , Apoptose , Sobrevivência Celular , Células Epiteliais/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Quinolizidinas , Espécies Reativas de Oxigênio , Pigmentos da Retina
12.
Mini Rev Med Chem ; 22(5): 729-742, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34488611

RESUMO

In this review, an effort towards presenting an all-around account of the recent progress on the natural product, aloperine, is made, and the antivirus structure-activity relationship of its derivatives is also summarized comprehensively. In addition, the principal pharmacological effects and corresponding molecular mechanisms of aloperine are discussed. Some new structural modifications of aloperine are also given, which might provide brief guidance for further investigations on the natural product aloperine.


Assuntos
Produtos Biológicos , Quinolizidinas , Produtos Biológicos/farmacologia , Piperidinas/química , Quinolizidinas/farmacologia , Relação Estrutura-Atividade
13.
Nat Prod Res ; 36(7): 1781-1788, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32924588

RESUMO

Seventeen quinolizidine alkaloids, including a new matrine-type one, sophcence A (1), were isolated from the roots of Sophora flavescens Alt. The structure of compound 1 was elucidated by means of 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The NMR data of (-)-Δ7-dehydrosophoramine (10) and oxy-N-methylcytisine (12) were reported for the first time. In addition, (+)-sophoranol (4) exhibited moderate inhibition on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages with IC50 value of 22.14 µM, while lupanine (17) was found to inhibit the growth of human glioma stem cells GSC-3# at 20 µg/mL.


Assuntos
Alcaloides , Quinolizidinas , Sophora , Alcaloides/química , Humanos , Lipopolissacarídeos/farmacologia , Raízes de Plantas/química , Quinolizidinas/farmacologia , Quinolizinas/química , Sophora/química
14.
Eur J Pharmacol ; 916: 174721, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34954231

RESUMO

Type 1 diabetes (T1D) is a metabolic dysfunction characterized by the selective destruction of islet ß-cells, with oxidative stress playing an essential role in the manifestation of this disease state. Aloperine (ALO) represents the main active alkaloid extracted from the traditional Chinese herbal Sophora alopecuroides L. and features outstanding antioxidative properties. In this study, T1D was induced by a single high dose streptozotocin (STZ, 150 mg/kg, intraperitoneal) in mice. Diabetic animals were intragastrically administered ALO at a dose of 50 mg/kg/day. Notably, treatment of ALO (50 mg/kg/day) for seven consecutive days could observably reverse the onset of diabetes induced by STZ accompanied by weight gain, lower blood glucose levels, and relief of ß-cells damage. Our in vitro study further demonstrated that ALO protected ß-cells from STZ/hydrogen peroxide-induced oxidative damage as manifested by increased expression of MnSOD and CAT. Furthermore, a network pharmacology study revealed that NOS1 represented the main target of ALO. Mechanistic studies subsequently showed that treatment of ALO increased the expression of NOS1, whereas NOS2 was decreased. Moreover, a docking study carried out suggested that ALO could fit into the binding pocket of human NOS1 and molecular dynamics simulation further validated this docking event. Collectively, the administration of ALO prior to diabetes could be a viable approach to the prevention of ß-cell injury. This study may offer a novel potential herbal medicine against T1D and may further help improve the understanding of the underlying molecular mechanisms of ALO-mediated protection against oxidative stress.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Óxido Nítrico Sintase Tipo I , Quinolizidinas , Animais , Glicemia/metabolismo , Citoproteção , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Camundongos , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo , Piperidinas/farmacologia , Quinolizidinas/administração & dosagem , Quinolizidinas/farmacologia , Quinolizidinas/uso terapêutico , Estreptozocina
15.
Chin J Nat Med ; 19(11): 815-824, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34844720

RESUMO

Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.


Assuntos
Neoplasias do Colo do Útero , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Retroalimentação , Feminino , Células HeLa , Humanos , Interleucina-6/genética , Janus Quinase 1 , Camundongos , Camundongos Nus , Quinolizidinas , Fator de Transcrição STAT3/genética , Transdução de Sinais , Neoplasias do Colo do Útero/tratamento farmacológico
16.
Bioorg Chem ; 117: 105432, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34678602

RESUMO

Twenty-nine 12 N-substituted aloperine derivatives were synthesized and screened for suppression on PD-L1 expression in H460 cells, as a continuation of our work. Systematic structural modifications led to the identification of compound 6b as the most active PD-L1 modulator. Compound 6b could significantly down-regulate both constitutive and inductive PD-L1 expression in NSCLC cells, and successively enhance the cytotoxicity of co-cultured T cells against tumor cells at the concentration of 20 µM. Also, it exhibited a moderate in vivo anticancer efficacy against Lewis tumor xenograft with a stable PK and safety profile. The mechanism study indicated that 6b mediated the degradation of PD-L1 through a proteasome pathway, rather than a lysosome route. These results provided the powerful information for cancer immunotherapy of aloperine derivatives with unique endocyclic skeleton by targeting PD-L1 to activate immune cells to kill cancer cells.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Quinolizidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Quinolizidinas/síntese química , Quinolizidinas/química , Relação Estrutura-Atividade
17.
Bioorg Chem ; 115: 105196, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34333425

RESUMO

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1ß, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.


Assuntos
Antivirais/farmacologia , Piperidinas/farmacologia , Quinolizidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Antivirais/toxicidade , Catepsina B/antagonistas & inibidores , Chlorocebus aethiops , Citocinas/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/toxicidade , Quinolizidinas/síntese química , Quinolizidinas/farmacocinética , Quinolizidinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Células Vero
18.
Int Immunopharmacol ; 97: 107720, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33945918

RESUMO

Presently, postmenopausal osteoporosis mainly caused by excessive activation of in vivo osteoclasts has become a global public health burden. Natural compounds have gradually become the potential drugs for the treatment of postmenopausal osteoporosis. Aloperine is a new alkaloid extracted from the leaves and seeds of sophora bean. The current studies have proved that aloperine has many biological activities, including anti-inflammatory, antiviral and anticancer activities. This study shows that aloperine can inhibit activity and formation of osteoclast mediated by RANKL in a dose-dependent manner without affecting the activity of bone marrow macrophages (BMM). In addition, it is found that aloperine can inhibit the expression of osteoclast specific marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), matrix metallopeptidase 9 (MMP9), cathepsin K (Ctsk), V-ATPase d2 and calcitonin receptor. The in vitro experiment of aloperine proved that aloperine can inhibit the degradation of IκBα and the phosphorylation of P65, ERK and JNK. Additionally, aloperine improves bone loss in ovariectomized (OVX) mice by inhibiting osteoclast activity. This project proved that aloperine can affect the formation of osteoclasts by inhibiting RANKL signaling channel, and it is indicated that aloperine has the potential to be developed as a new drug for the prevention and treatment of postmenopausal osteoporosis.


Assuntos
Osteogênese/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Quinolizidinas/farmacologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/patologia , Ovariectomia , Quinolizidinas/uso terapêutico , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Microtomografia por Raio-X
19.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800929

RESUMO

The main restraint obstructing the wider adoption of lupins as protein crops is the presence of bitter and toxic quinolizidine alkaloids (QAs), whose contents might increase under exposure to stressful environmental conditions. A poor understanding of how QAs accumulate hinders the breeding of sweet varieties. Here, we characterize the expression profiles of QA-related genes, along with the alkaloid content, in various organs of sweet and bitter narrow-leafed lupin (NLL, Lupinus angustifolius L.). Special attention is paid to the RAP2-7 transcription factor, a candidate regulator of the QA pathway. We demonstrate the upregulation of RAP2-7 and other QA-related genes, across the aerial organs of a bitter cultivar and the significant correlations between their expression levels, thus supporting the role of RAP2-7 as an important regulatory gene in NLL. Moreover, we showed that the initial steps of QA synthesis might occur independently in all aerial plant organs sharing common regulatory mechanisms. Nonetheless, other regulatory steps might be involved in RAP2-7-triggered QA accumulation, given its expression pattern in leaves. Finally, the examination of QA-related gene expression in plants infected with Colletotrichum lupini evidenced no connection between QA synthesis and anthracnose resistance, in contrast to the important role of polyamines during plant-pathogen interactions.


Assuntos
Colletotrichum/fisiologia , Regulação da Expressão Gênica de Plantas , Lupinus/genética , Doenças das Plantas/genética , Quinolizidinas/metabolismo , Cromatografia Gasosa , Lupinus/metabolismo , Lupinus/microbiologia , Especificidade de Órgãos , Melhoramento Vegetal , Doenças das Plantas/microbiologia , Proteínas de Plantas/biossíntese , Proteínas de Plantas/genética , Estruturas Vegetais/metabolismo , Estruturas Vegetais/microbiologia , Poliaminas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
20.
Biomolecules ; 11(3)2021 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805605

RESUMO

Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.


Assuntos
Alcaloides/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Inflamação/patologia , Quinolizinas/uso terapêutico , Células A549 , Alcaloides/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Quinolizidinas/farmacologia , Quinolizinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...