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1.
J Org Chem ; 86(19): 13381-13387, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34546728

RESUMO

Five dimeric Erythrina alkaloids, named erythrivarines J-N, were isolated from the barks of Erythrina variegata L. (Fabaceae). The erythrivarines J-L featured a 6/6/5/6/6/5/6/6/6 ring system and super conjugated double bond systems, causing intense color from blue to wine red, while erythrivarines M-N looked orange. The structures of the isolated compounds were elucidated by 1D and 2D NMR experiments combined with MS and confirmed by the X-ray crystal diffraction technique. The performed bioassay using HEI-OC-1 cells revealed neuroprotective properties of erythrivarine N against the hearing loss causing antibiotics, neomycin.


Assuntos
Alcaloides , Erythrina , Indolizinas , Fármacos Neuroprotetores , Alcaloides/farmacologia , Fármacos Neuroprotetores/farmacologia , Difração de Raios X
2.
J Org Chem ; 86(18): 12737-12744, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34459206

RESUMO

A mild and high efficient method to prepare indolizines by two-component reaction with the acid as the catalyst was developed. In this reaction, a new ring efficiently formed in one-step reaction. A wide range of substrates could be applied and the desired products were obtained in 8-95% yields under metal-free conditions. Different indolizine derivatives (compounds 3a-3n) were synthesized by general conditions and microwave irradiation conditions, and compound 3a gave the best results with an isolated yield of 95% and 82%, respectively. The structures of synthesized compounds were characterized by spectral analysis, and compound 3m was confirmed by single crystal X-ray analysis. UV-vis absorption and fluorescence properties of these compounds were correlated with substituent groups on indolizine rings.


Assuntos
Indolizinas , Pirazóis , Catálise , Estrutura Molecular , Espectrometria de Fluorescência
3.
J Org Chem ; 86(17): 11822-11834, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279948

RESUMO

To enhance the practicality of photouncaging system using 3-acyl-2-methoxyindolizines, direct acylation of indolizines with carboxylic acids was developed using condensation reagents, generally used for peptide coupling. This method allowed for caging a broad range of carboxylic acids with indolizines. The method enabled a facile synthesis of water-soluble caged bioactive carboxylic acids having an intramolecular photosensitizer. The efficient release of carboxylic acids from the synthesized caged compounds upon red light irradiation was confirmed in neutral buffered solutions.


Assuntos
Ácidos Carboxílicos , Indolizinas , Acilação , Luz , Peptídeos
4.
J Org Chem ; 86(15): 10235-10248, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34292727

RESUMO

A domino Michael-aldol double elimination route to indolizines having two different acyl groups at the C5 and C7 positions is described where chromone is employed as a two-carbon unit for the synthesis of a pyridine moiety for the first time. Various analogues were readily accessed in good yields under metal-free and eco-friendly conditions. Further manipulation of the resulting products allowed entry to novel indolizine-heterocycle adducts, which are difficult to access by other methods.


Assuntos
Cromonas , Indolizinas , Aldeídos , Piridinas
5.
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
6.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200764

RESUMO

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a-e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, ß = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Indolizinas/química , Anti-Inflamatórios/química , Cristalografia por Raios X/métodos , Ciclo-Oxigenase 2/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Indometacina/química , Relação Estrutura-Atividade
7.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206005

RESUMO

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood-brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.


Assuntos
Alcaloides/química , Antineoplásicos/síntese química , Indóis/química , Indolizinas/química , Fenantrenos/química , Fenantrolinas/química , Pró-Fármacos/síntese química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CHO , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Compostos de Amônio Quaternário/química , Relação Estrutura-Atividade
8.
J Enzyme Inhib Med Chem ; 36(1): 1472-1487, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34210233

RESUMO

A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Indolizinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Antituberculosos/química , Indolizinas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia
9.
J Org Chem ; 86(12): 8248-8262, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34061521

RESUMO

Erythrina alkaloids and their central nervous system effects have been studied for over a century, mainly due to their potent antagonistic actions at ß2-containing nicotinic acetylcholine receptors (nAChRs). In the present work, we report a synthetic approach giving access to a diverse set of Erythrina natural product analogues and present the enantioselective total synthesis of (+)-Cocculine and (+)-Cocculidine, both found to be potent antagonists of the ß2-containing nAChRs.


Assuntos
Alcaloides , Erythrina , Indolizinas , Receptores Nicotínicos , Alcaloides/farmacologia , Descoberta de Drogas
10.
Molecules ; 26(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066433

RESUMO

Candida albicans, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein ß-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.


Assuntos
Antifúngicos/síntese química , Ácidos Carboxílicos/síntese química , Teoria da Densidade Funcional , Simulação de Acoplamento Molecular , Antifúngicos/farmacocinética , Candida albicans , Ácidos Carboxílicos/farmacocinética , Química Farmacêutica/métodos , Desenho de Fármacos , Fluconazol/farmacologia , Ligação de Hidrogênio , Indolizinas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Quinolinas/síntese química , Quinolinas/farmacocinética , Termodinâmica
11.
Carbohydr Res ; 505: 108337, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34058545

RESUMO

The synthesis of novel indolizine C-nucleoside analogues has been achieved by the three-component coupling reaction of sugar alkynes, pyridines and α-bromo carbonyl compounds in one pot. The corresponding products are obtained in good to excellent yields. 49 examples have been given. The synthetic method is convenient, practical and efficient. It is suitable for various substrates including structurally diversified sugar alkynes with sensitive groups. The sugar alkynes include pyranosides, furanosides, and acyclic sugars. A plausible mechanism for the formation of indolizine C-nucleoside analogues has been elucidated.


Assuntos
Alcinos , Nucleosídeos , Indolizinas , Piridinas
12.
Viruses ; 13(5)2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946304

RESUMO

Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Antivirais/farmacologia , Reposicionamento de Medicamentos , Inibidores de Glicosídeo Hidrolases/farmacologia , Indolizinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , 1-Desoxinojirimicina/farmacologia , Células A549 , Animais , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Glicosilação/efeitos dos fármacos , Células HEK293 , Humanos , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Liberação de Vírus/efeitos dos fármacos
13.
Cell Death Dis ; 12(2): 179, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589591

RESUMO

Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Óxidos N-Cíclicos/farmacologia , Indolizinas/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Compostos de Piridínio/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Óxidos N-Cíclicos/administração & dosagem , Sinergismo Farmacológico , Feminino , Amplificação de Genes , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Indolizinas/administração & dosagem , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Oxazóis/administração & dosagem , Oxazóis/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Compostos de Piridínio/administração & dosagem , Quinazolinas/administração & dosagem , Quinazolinas/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Distribuição Aleatória , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Biomolecules ; 11(2)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530424

RESUMO

The anticancer activities of Withaferin-A (Wi-A) and Withanone (Wi-N) from Ashwagandha and Caffeic Acid Phenethyl Ester (CAPE) from honeybee propolis have been well documented. Here, we examined the binding potential of these natural compounds to inhibit the constitutive phosphorylation of epidermal growth factor receptors (EGFRs). Exon 20 insertion mutants of EGFR, which show resistance to various FDA approved drugs and are linked to poor prognosis of lung cancer patients, were the primary focus of this study. Apart from exon 20 insertion mutants, the potential of natural compounds to serve as ATP competitive inhibitors of wildtype protein and other common mutants of EGFR, namely L858R and exon19del, were also examined. The potential of natural compounds was compared to the positive controls such as erlotinib, TAS6417 and poziotinib. Similar to known inhibitors, Wi-A and Wi-N could displace and binds at the ATP orthosteric site of exon19del, L858R and exon20, while CAPE was limited to wildtype EGFR and exon 20 insertion mutants only. Moreover, the binding free energy of the natural drugs against EGFRs was also comparable to the positive controls. This computational study suggests that Wi-A and Wi-N have potential against multiple mutated EGFRs, warranting further in vitro and in vivo experiments.


Assuntos
Antineoplásicos/farmacologia , Ácidos Cafeicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Álcool Feniletílico/análogos & derivados , Vitanolídeos/farmacologia , Trifosfato de Adenosina/química , Biologia Computacional/métodos , Simulação por Computador , Dimerização , Receptores ErbB/biossíntese , Cloridrato de Erlotinib/farmacologia , Éxons , Deleção de Genes , Humanos , Indolizinas/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Álcool Feniletílico/farmacologia , Quinazolinas/farmacologia
15.
Eur J Cancer ; 145: 92-108, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33429148

RESUMO

BACKGROUND: Alhtough anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumour progression. METHODS: To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using the CRISPR/Cas9 knockout technique based on data mining across TCGA data sets and verified the candidate target in preclinical models and breast cancer high-throughput sequencing data sets. RESULTS: We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitise or resensitise HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumour tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harbouring a markedly shortened progression-free survival (PFS) (median PFS: 4.3 months versus 6.9 months; hazards ratio [HR] = 2.26 [95% confidence interval [CI] = 1.32-3.86]; P = 0.0028). CONCLUSIONS: Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitising or resensitising the tumours to anti-HER2 TKIs treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Óxidos N-Cíclicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Indolizinas/farmacologia , Lapatinib/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Compostos de Piridínio/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Biol Rep ; 48(1): 475-489, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33389483

RESUMO

We aimed to investigate whether resveratrol (RSV) could sensitize human triple-negative breast cancer (TNBC) cells to FL118-induced cell death, epithelial to mesenchymal transition (EMT), invasion, and migration. The effects of sequential administration of RSV and FL118 on MDA-MB-436 and MDA-MB-468 cells were evaluated in terms of cell viability, cytotoxicity, apoptosis, cell cycle distribution, active caspase-3/7 levels, migration and invasion. Furthermore, mRNA and protein levels of EMT associated genes and proteins were also evaluated. Sequential administration of RSV and FL118 inhibited the cell viability in both TNBC cell lines. Meanwhile sequential administration of RSV and FL118 also dramatically reduced the migratory and invasive capabilities, it also reversed the EMT process in both TNBC cells. Moreover, sequential administration of RSV and FL118 led to a significant increase of apoptotic cells, as well as active Caspase-3/7 levels. Sequential administration of RSV and FL118 caused TNBC cells accumulating in the G1 phase, and markedly suppressed the mRNA and protein levels of N-cadherin, ß-catenin, Vimentin, Snail, and Slug, and also significantly downregulated mRNA levels of Fibronectin, Twist1, Twist2, Zeb1, and Zeb2 genes, while enhanced the mRNA and protein levels of E-cadherin genes. RSV sensitized TNBC cells to FL118 via facilitating apoptosis, migration, invasion, and EMT and enhancing intracellular entrapment of FL118. Thus, our results suggest that since RSV enhanced the in vitro anticancer activity of FL118 in BC, it may be a potential therapeutic agent in advanced BC.


Assuntos
Benzodioxóis/farmacologia , Indolizinas/farmacologia , Proteínas de Neoplasias/genética , Resveratrol/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
17.
Glycobiology ; 31(4): 378-384, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-32985653

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.


Assuntos
1-Desoxinojirimicina/análogos & derivados , COVID-19/tratamento farmacológico , Indolizinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , 1-Desoxinojirimicina/farmacologia , Animais , COVID-19/virologia , Chlorocebus aethiops , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Células Vero
18.
Nat Prod Res ; 35(5): 763-769, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31079474

RESUMO

A new dibenzopyrrocoline alkaloid, (-)-grandifloramine (1), together with five known ones, actinodaphnine (2), N-methyllaurotetanine (3), boldine (4), lindcarpine (5), and (+)-norboldine (6), were isolated from Illigera grandiflora W. W. Sm. et J. F. Jeff. The structure of 1 was identified by HRESIMS, 1D/2D NMR, and electronic circular dichroism (ECD) spectra. Compound 1 and 2 exhibited the moderate inhibitory activity against acetylcholinesterase and 3 showed moderate butyrylcholinesterase inhibitory activity. This is the first report of the chemical constituents of I. grandiflora.


Assuntos
Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Hernandiaceae/química , Indolizinas/farmacologia , Acetilcolinesterase/metabolismo , Alcaloides/química , Butirilcolinesterase/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Dicroísmo Circular , Espectroscopia de Ressonância Magnética , Espectroscopia de Prótons por Ressonância Magnética
19.
Nat Prod Res ; 35(3): 440-446, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31264906

RESUMO

The total synthesis of both the double bond isomers of indolizine alkaloid 8-deoxypumiliotoxin 193H has been accomplished. Both the double bond isomers Z-4 and E-4 induced convulsions and inhibited neuro-muscular activity at a dose of 25 mg/kg after intraperitoneal injection in mice. The lethal dose of Z-4 and E-4 was 100 mg/kg, indicating that 8-deoxypumiliotoxin 193H is 10-times less toxic than the known pumiliotoxin (+)-251 D.


Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Força Muscular/efeitos dos fármacos , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/toxicidade , Animais , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Indolizinas/química , Indolizinas/farmacologia , Injeções Intraperitoneais , Isomerismo , Masculino , Camundongos Endogâmicos , Piperidinas/química , Piperidinas/farmacologia , Teste de Desempenho do Rota-Rod , Convulsões/induzido quimicamente , Relação Estrutura-Atividade
20.
Bioorg Med Chem ; 29: 115848, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33189508

RESUMO

Owing to its potential biological relevance, DNA G-quadruplex has been considered as a prospective anti-cancer target. Some known G-quadruplex-interactive N-containing compounds with low cytotoxicity have become prospective anticancer drugs. Here we reported a new type of N-containing alkaloids 3,8a-disubstituted indolizinones, and investigated their substituent effects at 3- and 8a-positions in targeting to DNA c-myc G-quadruplex. And then we used 3-naphtyl-8a-(pyridin-2-yl) substrate I8 as an example, and investigated its ability in targeting to DNA parallel G-quadruplexes in vitro.


Assuntos
Antineoplásicos/química , DNA de Neoplasias/análise , Indolizinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA de Neoplasias/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Quadruplex G , Humanos , Indolizinas/síntese química , Indolizinas/farmacologia , Estrutura Molecular , Proteínas Proto-Oncogênicas c-myc/análise , Proteínas Proto-Oncogênicas c-myc/genética , Espectrometria de Fluorescência , Relação Estrutura-Atividade
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