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1.
Biochem Biophys Res Commun ; 604: 165-171, 2022 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-35306249

RESUMO

Bladder cancer (BC) is a common malignancy of the urological system that still lacks effective treatment. It is frequently characterised by dysregulation of fibroblast growth factor receptor (FGFR) signalling. FGFR inhibitors have been proven as a promising treatment for BC in clinical settings. Besides the FGFR signalling, the therapeutic effects of FGFR inhibitors are often limited owing to various mechanisms, such as the activation of the Akt signalling pathway. Therefore, this study aimed to examine the synergistic effects of ipatasertib, a FGFR inhibitor, and erdafitinib, an Akt inhibitor, in BC cells. Ipatasertib and erdafitinib co-treatment synergistically inhibited cell proliferation and induced BC cell death. Mechanically, ipatasertib and erdafitinib induced the activation of Bax, an essential protein for cell death. Moreover, erdafitinib, which inhibited the Akt signalling pathway, is responsible for Bim upregulation, a condition critical to achieving the synergistic effects. Therefore, our data suggest that ipatasertib and erdafitinib co-treatment is a promising strategy for BC.


Assuntos
Apoptose , Proteína 11 Semelhante a Bcl-2 , Mitocôndrias , Piperazinas , Pirazóis , Pirimidinas , Quinoxalinas , Neoplasias da Bexiga Urinária , Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinoxalinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
2.
Arch Pharm (Weinheim) ; 355(5): e2100448, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35174890

RESUMO

We synthesized multiple cinnamils and quinoxalines to evaluate their anticancer activity. Cinnamils were used as precursors for quinoxalines via condensation with 1,2-diaminobenzene. Among the 26 synthesized compounds reported in this article, we found that cinnamil 3l exhibited its inhibitory effect with an IC50 value of 1.45 ± 0.98 µM, significantly higher than doxorubicin (8.5 ± 0.85 µM) against pancreatic cancer cells (PANC-1). Additionally, cinnamil 3l (IC50 10.98 ± 3.63 µM) showed less cytotoxicity than doxorubicin to Hs68 cells (0.92 ± 1.11 µM). The colony formation assay demonstrated that 3l obviously decreased the PANC-1 cell viability, and Western blot assays confirmed that 3l markedly induced apoptosis of PANC-1 cells through Bax, Bcl-2, and caspase 3 signaling cascades. These results demonstrate that cinnamil 3l has great potential to be further developed as a promising chemotherapeutic agent for pancreatic cancer.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
3.
Arch Pharm (Weinheim) ; 355(5): e2100454, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35174895

RESUMO

Cancer is the world's foremost cause of death. There are over 100 different forms of cancer. Cancers are frequently named after the organs or tissues in which they develop. As a part of our aim to develop promising anticancer agents, a series of new indeno[1,2-b]quinoxaline derivatives were synthesized. All of the synthesized compounds were tested for anticancer activity in vitro in three human cancer cell lines: the HCT-116 colon cancer cell line, the HepG-2 liver cancer cell line, and the MCF-7 breast cancer cell line. Among the tested derivatives, 2, 3, 5, 12, 21, and 22 showed exceptional antiproliferative activities against the three tested cell lines compared to the reference standard imatinib. These compounds were, therefore, selected for further investigations. Evaluation of their cytotoxicity against a normal human cell line (WI-38) was performed, to ensure their safety and selectivity (IC50 > 92 µM). Then, induction of apoptosis by the most active compounds was found to be accomplished by downregulation of Bcl-2 and upregulation of BAX and caspase-3. After that, the most promising apoptotic compound that increases the caspase-3 and BAX expression and downregulates Bcl-2 activity (3) was assessed for its impact on the cell cycle distribution in HepG-2 cells: The most potent derivative (3) induced cell cycle arrest at the G2/M phase. Finally, in silico evaluation of the ADME properties indicated that compound 3 is orally bioavailable and can be readily synthesized on a large scale.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia
4.
J Mol Biol ; 434(9): 167503, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35183560

RESUMO

Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and synthesis, enzyme inhibition assays, co-crystallography, and structural analysis. A panel of inhibitors in matched pairs were designed with and without P4 cap fluorination, tested against WT protease and the D168A resistant variant, and a total of 22 high-resolution co-crystal structures were determined. While fluorination did not significantly improve potency against the WT protease, PIs with fluorinated P4 caps retained much better potency against the D168A protease variant. Detailed analysis of the co-crystal structures revealed that PIs with fluorinated P4 caps can sample alternate binding conformations that enable adapting to structural changes induced by the D168A substitution. Our results elucidate molecular mechanisms of fluorine-specific inhibitor interactions that can be leveraged in avoiding drug resistance.


Assuntos
Ácidos Aminoisobutíricos , Ciclopropanos , Desenho de Fármacos , Farmacorresistência Viral , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas , Sulfonamidas , Proteases Virais , Ácidos Aminoisobutíricos/química , Ácidos Aminoisobutíricos/farmacologia , Ciclopropanos/química , Ciclopropanos/farmacologia , Farmacorresistência Viral/genética , Flúor/química , /farmacologia , Halogenação , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Leucina/química , Leucina/genética , Leucina/farmacologia , Prolina/química , Prolina/genética , Prolina/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteases Virais/química , Proteases Virais/genética
5.
Neuroreport ; 33(4): 199-203, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35143451

RESUMO

OBJECTIVE: Numerous studies suggest that the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA) receptor appears to play a central role in mediating brain functions, such as learning and memory. Trafficking of this receptor is related to different long-term memory processes. This study explores the role of two AMPA receptor (AMPAR) modulators in object recognition memory (ORM) reconsolidation. METHODS: First, the effects of immediate administration of each drug after memory reactivation were investigated and compared. Then, this drug's efficient time window and its effects without memory reactivation were investigated. RESULTS: Immediate CX546 administration after reactivation did not affect ORM reconsolidation. In contrast, administration of 10-mg/kg NBQX significantly impaired ORM reconsolidation within a 6-h time window. Importantly, the observed effects were not attributed to the exploratory behavior or locomotor activity of mice. CONCLUSION: These findings provide new evidence that the AMPA receptor plays an important role in the reconsolidation phase of ORM.


Assuntos
Consolidação da Memória , Memória de Longo Prazo , Receptores de AMPA , Reconhecimento Psicológico , Animais , Dioxóis/farmacologia , Aprendizagem , Camundongos , Piperidinas/farmacologia , Quinoxalinas/farmacologia , Receptores de AMPA/fisiologia
6.
Org Lett ; 24(9): 1859-1864, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35225627

RESUMO

With control by N1-substituents, the switchable divergent C-H functionalization reaction of quinoxalin-2(1H)-ones is achieved for the synthesis of (Z)-enaminones and furo[2,3-b]quinoxalines using the combination of a copper catalyst and an oxidant. This new protocol features mild reaction conditions, readily available materials, and a broad substrate scope. Gram-scale and mechanistic studies were also investigated. Furthermore, the desired products exhibited excellent antitumor activity against A549, HepG-2, MCF-7, and HeLa cells, which were tested by MTT assay.


Assuntos
Alcinos , Quinoxalinas , Catálise , Cobre , Células HeLa , Humanos , Estrutura Molecular , Quinoxalinas/farmacologia
7.
Biochem Biophys Res Commun ; 595: 7-13, 2022 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-35091109

RESUMO

The intestinal tract is an essential component of the body's immune system, and is extremely sensitive to exposure of ionizing radiation. While ionizing radiation can effectively induce multiple forms of cell death, whether it can also promote ferroptosis in intestinal cells and the possible interrelationship between ferroptosis and intestinal immune function has not been reported so far. Here, we found that radiation-induced major ultrastructural changes in mitochondria of small intestinal epithelial cells and the changes induced in iron content and MDA levels in the small intestine were consistent with that observed during cellular ferroptosis, thus suggesting occurrence of ferroptosis in radiation-induced intestinal damage. Moreover, radiation caused a substantial increase in the expression of ferroptosis-related factors such as LPCAT3 and ALOX15 mRNA, augmented the levels of immune-related factors INF-γ and TGF-ß mRNA, and decreased the levels of IL-17 mRNA thereby indicating that ionizing radiation induced ferroptosis and impairment of intestinal immune function. Liproxstatin-1 is a ferroptosis inhibitor that was found to ameliorate radiation-induced ferroptosis and promote the recovery from immune imbalances. These findings supported the role of ferroptosis in radiation-induced intestinal immune injury and provide novel strategies for protection against radiation injury through regulation of the ferroptosis pathway.


Assuntos
Ferroptose/fisiologia , Intestinos/patologia , Quinoxalinas/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Radiação Ionizante , Compostos de Espiro/farmacologia , 1-Acilglicerofosfocolina O-Aciltransferase/genética , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/efeitos da radiação , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Glutationa/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/efeitos da radiação , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/efeitos da radiação , Mitocôndrias/ultraestrutura , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo
8.
Sci Rep ; 12(1): 679, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027605

RESUMO

A novel nucleotide mutation in ACC1 resulting in an alanine to valine amino acid substitution in acetyl-CoA carboxylase (ACCase) at position 2004 of the Alopecurus myosuroides reference sequence (A2004V) imparts quizalofop resistance in wheat. Genotypes endowed with the homozygous mutation in one or two ACC1 homoeologs are seven- and 68-fold more resistant to quizalofop than a wildtype winter wheat in greenhouse experiments, respectively. In vitro ACCase activities in soluble protein extracts from these varieties are 3.8- and 39.4-fold more resistant to quizalofop with the homozygous mutation in either one or two genomes, relative to the wildtype. The A2004V mutation does not alter the specific activity of wheat ACCase, suggesting that this resistance trait does not affect the catalytic functions of ACCase. Modeling of wildtype and quizalofop-resistant wheat ACCase demonstrates that the A2004V amino acid substitution causes a reduction in the volume of the binding pocket that hinders quizalofop's interaction with ACCase. Docking studies confirm that the mutation reduces the binding affinity of quizalofop. Interestingly, the models suggest that the A2004V mutation does not affect haloxyfop binding. Follow up in vivo and in vitro experiments reveal that the mutation, in fact, imparts negative cross-resistance to haloxyfop, with quizalofop-resistant varieties exhibiting higher sensitivity to haloxyfop than the wildtype winter wheat line.


Assuntos
Acetil-CoA Carboxilase/química , Acetil-CoA Carboxilase/genética , Substituição de Aminoácidos , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Propionatos/farmacologia , Quinoxalinas/farmacologia , Triticum/efeitos dos fármacos , Acetiltransferases/genética , Alanina , Mutação , Proteínas de Plantas , Poaceae , Piridinas/farmacologia , Valina
9.
J Enzyme Inhib Med Chem ; 37(1): 573-591, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35012403

RESUMO

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrobenzenos/síntese química , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Arch Pharm (Weinheim) ; 355(2): e2100359, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34862634

RESUMO

Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.


Assuntos
Antineoplásicos/farmacologia , Quinoxalinas/farmacologia , Triazóis/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Simulação por Computador , Feminino , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Quinoxalinas/síntese química , Quinoxalinas/química , Ratos , Sorafenibe/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
11.
Eur J Med Chem ; 229: 113995, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34802835

RESUMO

Cooperative disruption of Watson-Crick hydrogen bonds, as well as base-destacking, is shown to be triggered by a quinoxaline-based small molecule consisting of an N,N-dimethylaminopropyl tether, and a para-substituted benzyl moiety. This events lead to superstructure formation and DNA condensation as evident from biophysical experiments and classical molecular dynamics simulations. The DNA superstructure formation by mono-quinoxaline derivatives is highly entropically favored and predominantly driven by hydrophobic interactions. Furthermore, oversupercoiling of DNA and base-destacking cumulatively induces histone eviction from in-vitro assembled nucleosomes at lower micromolar concentrations implicating biological relevance. The DNA structural modulation and histone eviction capacity of the benzyl para-substituents are in the order: -I > -CF3> -Br > -Me > -OMe > -OH, which is largely guided by the polarity of benzyl para-substituent and the resulting molecular topology. The most hydrophobic derivative 3c with para-iodo benzyl moiety causes maximal disruption of base pairing and generation of superstructures. Both these events gradually diminish as the polarity of the benzyl para-substituent increases. On the other hand, quinoxaline derivatives having heterocyclic ring instead of benzyl ring, or in the absence of N,N-dimethylamino head-group, is incapable of inducing any DNA structural change and histone eviction. Further, the quinoxaline compounds displayed potent anticancer activities against different cancer cell lines which directly correlates with the hydrophobic effects of the benzyl para-substituents. Overall, the present study provides new insights into the mechanistic approach of DNA structural modulation driven histone eviction guided by the hydrophobicity of synthesized compounds leading to cellular cytotoxicity towards cancer cells.


Assuntos
DNA/química , Histonas/metabolismo , Quinoxalinas/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Conformação Molecular , Teoria Quântica , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Termodinâmica
12.
Gut ; 71(3): 627-642, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33833066

RESUMO

OBJECTIVE: HCV-genotype 4 infections are a major cause of liver diseases in the Middle East/Africa with certain subtypes associated with increased risk of direct-acting antiviral (DAA) treatment failures. We aimed at developing infectious genotype 4 cell culture systems to understand the evolutionary genetic landscapes of antiviral resistance, which can help preserve the future efficacy of DAA-based therapy. DESIGN: HCV recombinants were tested in liver-derived cells. Long-term coculture with DAAs served to induce antiviral-resistance phenotypes. Next-generation sequencing (NGS) of the entire HCV-coding sequence identified mutation networks. Resistance-associated substitutions (RAS) were studied using reverse-genetics. RESULT: The in-vivo infectious ED43(4a) clone was adapted in Huh7.5 cells, using substitutions identified in ED43(Core-NS5A)/JFH1-chimeric viruses combined with selected NS5B-changes. NGS, and linkage analysis, permitted identification of multiple genetic branches emerging during culture adaptation, one of which had 31 substitutions leading to robust replication/propagation. Treatment of culture-adapted ED43 with nine clinically relevant protease-DAA, NS5A-DAA and NS5B-DAA led to complex dynamics of drug-target-specific RAS with coselection of genome-wide substitutions. Approved DAA combinations were efficient against the original virus, but not against variants with RAS in corresponding drug targets. However, retreatment with glecaprevir/pibrentasvir remained efficient against NS5A inhibitor and sofosbuvir resistant variants. Recombinants with specific RAS at NS3-156, NS5A-28, 30, 31 and 93 and NS5B-282 were viable, but NS3-A156M and NS5A-L30Δ (deletion) led to attenuated phenotypes. CONCLUSION: Rapidly emerging complex evolutionary landscapes of mutations define the persistence of HCV-RASs conferring resistance levels leading to treatment failure in genotype 4. The high barrier to resistance of glecaprevir/pibrentasvir could prevent persistence and propagation of antiviral resistance.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatócitos/virologia , Mutação/genética , Benzimidazóis/farmacologia , Técnicas de Cultura de Células , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sofosbuvir/farmacologia , Sulfonamidas/farmacologia
13.
Mini Rev Med Chem ; 22(1): 15-25, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33573542

RESUMO

BACKGROUND: For decades, the quinoxaline 1,4-di-N-oxide ring has been considered a privileged structure to develop new antibacterial, antitumoural, and antiprotozoal agents, among others; however, its mechanism of action is not clear. OBJECTIVE: The main aim of this mini-review was to analyze the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives reported as antibacterial, antitumoural, and antiprotozoal agents. RESULTS: Initially, the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives against bacteria, tumoural cell lines, and parasites have been described as nonspecific, but recently, the results against different organisms have shown that these compounds have an inhibitory action on specific targets such as trypanothione reductase, triosephosphate isomerase, and other essential enzymes. CONCLUSION: In summary, quinoxaline 1,4-di-N-oxide is a scaffold to develop new anti- Mycobacterium tuberculosis, antitumoural and antiprotozoal agents; however, understanding the mechanism of action of quinoxaline 1,4-di-N-oxide derivatives in each microorganism could contribute to the development of new and more potent selective drugs.


Assuntos
Mycobacterium tuberculosis , Óxidos , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
14.
Pest Manag Sci ; 78(3): 938-946, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34719096

RESUMO

BACKGROUND: 4-Hydroxyphenyl pyruvate dioxygenase (EC 1.13.11.27, HPPD) is one of the important target enzymes used to address the issue of weed control. HPPD-inhibiting herbicides can reduce the carotenoid content in plants and hinder photosynthesis, eventually causing albinism and death. Exploring novel HPPD-inhibiting herbicides is a significant direction in pesticide research. In the process of exploring new high-efficiency HPPD inhibitors, a series of novel quinoxaline derivatives were designed and synthesized using an active fragment splicing strategy. RESULTS: The title compounds were unambiguously characterized by infrared, 1 H NMR, 13 C NMR, and high-resolution mass spectroscopy. The results of the in vitro tests indicated that the majority of the title compounds showed potent inhibition of Arabidopsis thaliana HPPD (AtHPPD). Preliminary bioevaluation results revealed that a number of novel compounds displayed better or excellent herbicidal activity against broadleaf and monocotyledonous weeds. Compound III-5 showed herbicidal effects comparable to those of mesotrione at a rate of 150 g of active ingredient (ai)/ha for post-emergence application. The results of molecular dynamics verified that compound III-5 had a more stable protein-binding ability. Molecular docking results showed that compound III-5 and mesotrione shared homologous interplay with the surrounding residues. In addition, the enlarged aromatic ring system adds more force, and the hydrogen bond formed can enhance the synergy with π-π stacking. CONCLUSIONS: The present work indicates that compound III-5 may be a potential lead structure for the development of new HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase , Herbicidas , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinoxalinas/farmacologia , Relação Estrutura-Atividade
15.
Chem Biol Interact ; 352: 109779, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34922904

RESUMO

Growing evidence shows that cancer progression links with both heterogeneity of the tumor microenvironment and dysregulated activity of immune cells. Cancer-secreted exosomes are being recognized as indispensable mediators of the exchange cargo between cancer and immune cells. The M2-phenotype tumor-associated macrophages have the function of promoting tumor progression and drug resistance. Diffuse large B-cell lymphoma(DLBCL) is a highly heterogeneous and very common malignant non-Hodgkin's lymphoma. Here, we demonstrate that different subtype DLBCL cell-derived exosomes are internalized by macrophages, which can affect macrophages polarization. The mechanism of DLBCL-derived exosomes on macrophage polarization remains unclear currently. This study showed that DLBCL-secreted exosomes could induce the transformation of macrophages to a protumor M2-like phenotype, and block the drug-induced apoptosis of DLBCL cells in an indirect co-culture system. Different DLBCL-derived exosomes could change the phenotype of macrophages through the STAT3 signaling, which upregulated the expression of oncogenic genes and classical markers of M2-like phenotype macrophages, such as IL-10, CD206, and CD163. The addition of DLBCL-derived exosomes resulted in the activation of the STAT3 signaling pathway of M0/M2 macrophages in an indirect co-culture system. GP130 was highly enriched in DLBCL-derived exosomes, which triggered the activation of STAT3 of macrophages and subsequently induced the downstream targets such as BCL2, SURVIVIN, and BAX. The parallel changes of STAT3 and GP130 in macrophages confirmed that GP130 of DLBCL-derived exosomes promoted macrophage polarization by activating STAT3 signaling. Furthermore, all of these effects could be reversed by the GP130 inhibitor SC144. The data indicated that DLBCL-derived exosomes could trigger macrophages polarization into a pro-survival M2-like phenotype, which was at least partially through the GP130/STAT3 signaling pathway. Collectively, this study showed that DLBCL-derived exosomes could promote macrophages transformation to protumor M2-like phenotype in the tumor microenvironment.


Assuntos
Receptor gp130 de Citocina/imunologia , Exossomos/imunologia , Exossomos/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Fator de Transcrição STAT3/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Receptor gp130 de Citocina/antagonistas & inibidores , Humanos , Hidrazinas/farmacologia , Imunofenotipagem , Modelos Biológicos , Fenótipo , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/classificação
16.
Eur J Med Chem ; 227: 113915, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34695777

RESUMO

Fifteen pyridazino-pyrrolo-quinoxalinium salts were synthesized and tested for their antiprotozoal activity against Leishmania infantum amastigotes. Eleven of them turned out to be leishmanicidal, with EC50 values in the nanomolar range, and displayed low toxicity against the human THP-1 cell line. Selectivity indices for these compounds range from 10 to more than 1000. Compounds 3b and 3f behave as potent inhibitors of the oxidoreductase activity of the essential enzyme trypanothione disulfide reductase (TryR). Interestingly, binding of 3f is not affected by high trypanothione concentrations, as revealed by the noncompetitive pattern of inhibition observed when tested in the presence of increasing concentrations of this substrate. Furthermore, when analyzed at varying NADPH concentrations, the characteristic pattern of hyperbolic uncompetitive inhibition supports the view that binding of NADPH to TryR is a prerequisite for inhibitor-protein association. Similar to other TryR uncompetitive inhibitors for NADPH, 3f is responsible for TryR-dependent reduction of cytochrome c in a reaction that is typically inhibited by superoxide dismutase.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania infantum/efeitos dos fármacos , NADH NADPH Oxirredutases/antagonistas & inibidores , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Leishmania infantum/metabolismo , Estrutura Molecular , NADH NADPH Oxirredutases/metabolismo , Testes de Sensibilidade Parasitária , Piridazinas/química , Piridazinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade , Células THP-1
17.
Bioorg Chem ; 118: 105480, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34823196

RESUMO

A well-structured in silico workflow is here reported for disclosing structure-based pharmacophore models against bromodomain-containing protein 9 (BRD9), accelerating virtual screening campaigns and facilitating the identification of novel binders. Specifically, starting from 23 known ligands co-crystallized with BRD9, three-dimensional pharmacophore models, namely placed in a reference protein structure, were developed. Specifically, we here introduce a fragment-related pharmacophore model, useful for the identification of new promising small chemical probes targeting the protein region responsible of the acetyllysine recognition, and two further pharmacophore models useful for the selection of compounds featuring drug-like properties. A pharmacophore-driven virtual screening campaign was then performed to facilitate the selection of new selective BRD9 ligands, starting from a large library of commercially available molecules. The identification of a promising BRD9 binder (7) prompted us to re-iterate this computational workflow on a second focused in-house built library of synthesizable compounds and, eventually, three further novel BRD9 binders were disclosed (8-10). Moreover, all these compounds were tested among a panel comprising other nine bromodomains, showing a high selectivity for BRD9. Preclinical bioscreens for potential anticancer activity highlighted compound 7 as that showing the most promising biological effects, proving the reliability of this in silico pipeline and confirming the applicability of the here introduced structure-based three-dimensional (3D) pharmacophore models as straightforward tools for the selection of new BRD9 ligands.


Assuntos
Descoberta de Drogas , Quinoxalinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
18.
Behav Brain Res ; 418: 113631, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34715146

RESUMO

The dorsolateral striatum (DLS) is involved in addiction, reward, and alcohol related behaviors. The DLS primarily receives excitatory inputs which are gated by post-synaptic AMPA receptors. We antagonized AMPA receptors in the DLS to investigate how such modulation affects binge-like alcohol drinking in male and female C57BL/6J mice and whether an associated alcohol drinking history alters dorsomedial striatum (DMS) and DLS AMPA receptor expression. We also investigated the effect of intra-DLS NBQX on locomotor activity and saccharin drinking in mice. Mice were allowed free access to 20% alcohol for two hours each day for a total of seven days. Mice received an intra-DLS infusion of one of four concentrations of NBQX (saline, 0.15, 0.5, or 1.5 µg/side), an AMPA receptor antagonist, immediately prior to alcohol access on day 7. Two-hour binge alcohol intakes, locomotor activity, and blood alcohol concentrations were determined. Intra-DLS NBQX reduced binge-like alcohol drinking in a U-shaped manner in male and female mice. Intake predicted blood alcohol concentration, and locomotor activity was not affected. In a follow up experiment, we assessed whether the most effective NBQX concentration for reducing alcohol consumption also reduced saccharin drinking, finding intra-DLS NBQX did not alter saccharin drinking in male and female mice. These data suggest that AMPA receptors in the DLS play a role in the modulation of binge-like alcohol drinking. These findings further validate the importance of the DLS for alcohol related behaviors and alcohol use disorder.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neostriado/metabolismo , Quinoxalinas/farmacologia , Receptores de AMPA/antagonistas & inibidores , Animais , Concentração Alcoólica no Sangue , Feminino , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Sacarina/administração & dosagem
19.
Bull Exp Biol Med ; 172(2): 146-150, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34855082

RESUMO

We studied the role of JNK in the regulation of the metabolism of xenobiotic venlafaxine by liver cells under in vitro conditions. The inhibitory role of this protein kinase in the biotransformation of this psychotropic agent by hepatocytes was demonstrated. JNK inhibitor added to the liver homogenate containing antidepressant enhanced and accelerated the formation of the only pharmacologically active venlafaxine metabolite O-desmethylvenlafaxine in the cell suspension. The results show the promise of studying modifiers of activity of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop a fundamentally new approach to control the transformation of xenobiotics and to create a new class of pharmaceutical, target regulators of drugs metabolism.


Assuntos
Hepatócitos/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Xenobióticos/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Succinato de Desvenlafaxina/metabolismo , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacologia , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Cloridrato de Venlafaxina/metabolismo
20.
FEMS Microbiol Lett ; 368(19)2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34724043

RESUMO

The issue of food contamination by fungi and aflatoxins; constitutes a serious concern not only for human/animal health but also for agriculture and the economy. Aflatoxins are secondary metabolites produced by certain filamentous fungi and contaminate a variety of foodstuffs. In this context, control of fungal growth and aflatoxin contamination appears to be important. The present study aimed to investigate new Cu(I) and Cu(II)-quinoxaline complexes, namely [Cu(2,2´-pq)(NO3)](NO3) (1), [Cu(2,2´-pq)2(NO3)](NO3)·6H2O (2) and [Cu(2,2΄-pq)2](BF4) (3), where 2,2´-pq is 2-(2'-pyridyl quinoxaline), as antifungal agents against Aspergillus parasiticus. All complexes, the ligand and the starting material Cu(NO3)2-3H2O, regardless of the concentration used, caused inhibition of A. parasiticus growth ranged from 8.52 to 33.33%. The fungal growth inhibition was triggered when irradiation in visible (λ > 400 nm) was continuously applied (range 18.36-57.20%). The highest inhibitory activity was exhibited by the complex [Cu(2,2´-pq)2(NO3)](NO3)·6H2O and for this reason, it was selected to be studied for its ability to suppress aflatoxin B1 produced by A. parasiticus. AFB1 production after the irradiation process was found to be suppressed by 25% compared to AFB1 produced in dark conditions.


Assuntos
Antifúngicos , Aspergillus , Aflatoxina B1/química , Aflatoxinas/antagonistas & inibidores , Animais , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/efeitos da radiação , Cobre/química , Humanos , Luz , Quinoxalinas/farmacologia
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