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1.
Eur J Med Chem ; 181: 111583, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400710

RESUMO

3-(Alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones (4-9) have been designed using Ellipticine structure as a model, replacing the carbazole core and the pyridine ring with a dibenzothiophene and a pyrimidine moiety, respectively. New benzothienoquinazolinones (4-9) have been synthesized by a simple one-pot reaction employing 3-aminodibenzothiophene as starting material. The benzothienoquinazolinones obtained (4-9), were evaluated for their anticancer activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. The results revealed that compounds 4 and 7 presented a good antitumor activity toward the triple negative MDA-MB-231, without cytotoxicity against non-tumoral cells. Furthermore, the compounds 4 and 7 can be considered important molecular multi-target tools for their dual inhibition of different cellular proteins, i.e. Tubulin and human Topoisomerase I, involved in relevant cellular processes, as predicted by in silico studies and demonstrated by in vitro assays (for compound 4).


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Desenho de Drogas , Feminino , Humanos , Simulação de Acoplamento Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Inibidores da Topoisomerase I/química , Moduladores de Tubulina/química
2.
Cancer Invest ; 37(7): 311-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412710

RESUMO

Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.


Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/genética , Purinas/farmacologia , Quinazolinonas/farmacologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
3.
Eur J Med Chem ; 182: 111575, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415900

RESUMO

We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 µg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Quinazolinonas/farmacologia , Amebicidas/síntese química , Amebicidas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
4.
Expert Rev Clin Pharmacol ; 12(9): 831-840, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356117

RESUMO

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting. Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC. Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinonas/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Intervalo Livre de Progressão , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Taxa de Sobrevida
5.
Eur J Med Chem ; 175: 287-308, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096152

RESUMO

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 µg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 µg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4'c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 µg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 µg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinazolinonas/síntese química , Quinazolinonas/farmacologia , Animais , Antibacterianos/química , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Quinazolinonas/química , Relação Estrutura-Atividade , Células Vero
6.
Vet Parasitol ; 269: 57-64, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31079829

RESUMO

The objective of this study was to compare the effect of non-GMO Saccharomyces cerevisiae fermentation products (SCFP) with that of a halofuginone treatment against Cryptosporidium parvum infection in pre-weaned calves on a commercial dairy farm. A total of 123 neonatal female calves, housed in individual hutches, were enrolled sequentially based on date of birth in 41 blocks of 3 animals each. Calves within each block were allocated to one of 3 treatments: remaining untreated, fed with SCFP (Diamond V SmartCare® at 1 g/d in milk and NutriTek® at 5 g/d in starter grain) for the first 63 days of life, or treated with halofuginone (0.1 mg/kg/d) for the first 7 days of life. Fecal samples collected on days 4-21 post-partum were examined for both Cryptosporidium oocysts and coproantigen. The presence and intensity of diarrhea were monitored by scoring daily for the first 4 weeks of life. Calves were weighed at 0, 21, 42 and 63 days of age. Almost all calves were Cryptosporidium-positive at least once during the study. Halofuginone significantly reduced the number of Cryptosporidium-positive fecal samples as compared to the two other groups. Based on the coproantigen scores, both halofuginone and SCFP feeding significantly reduced the intensity of Cryptosporidium infection as compared to the untreated group. Diarrhea was recorded in almost all calves at least once. Neither the proportion of diarrheic calves nor the intensity and duration of diarrhea differed among the 3 treatment groups significantly. The mean daily weight gain during the first 3 weeks of life was significantly lower in halofuginone treated calves than in both other groups; however, at the end of the study period the total weight gain did not significantly differ among the 3 treatment groups. In conclusion, the clinical results and weight gains of pre-weaning supplementation with the SCFP were neither better nor worse than the 7-day halofuginone treatment suggesting that the SCFP feeding may be from the clinical point of view a natural alternative measure, instead of halofuginone treatment, in bovine cryptosporidiosis.


Assuntos
Doenças dos Bovinos/prevenção & controle , Criptosporidiose/prevenção & controle , Cryptosporidium parvum/efeitos dos fármacos , Aditivos Alimentares/farmacologia , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Saccharomyces cerevisiae/metabolismo , Animais , Animais Recém-Nascidos , Bovinos , Doenças dos Bovinos/parasitologia , Estudos de Coortes , Criptosporidiose/parasitologia , Diarreia/parasitologia , Diarreia/prevenção & controle , Diarreia/veterinária , Fezes/parasitologia , Feminino , Fermentação , Estudos Longitudinais , Oocistos , Prevalência , Fatores de Tempo , Ganho de Peso/efeitos dos fármacos
7.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137460

RESUMO

The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and ß-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit ß-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843's anticonvulsive effects and suggest a possible involvement of ß-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.


Assuntos
Encéfalo/metabolismo , Excitação Neurológica , Receptores de Grelina/agonistas , Animais , Benzazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Agonistas de Dopamina/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Grelina/antagonistas & inibidores , Triazóis/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , beta-Arrestinas/farmacologia
8.
Eur J Med Chem ; 176: 41-49, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31091479

RESUMO

Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC50 values of 1.54 µM and 0.71 µM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC50 values of 1.90 and 0.84 µM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Quinazolinonas/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Sítios de Ligação , Replicação do DNA/efeitos dos fármacos , Células Hep G2 , Antígenos do Núcleo do Vírus da Hepatite B/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade
9.
Drugs ; 79(8): 823-831, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069718

RESUMO

The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Intervalo Livre de Doença , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Humanos , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Qualidade de Vida , Quinazolinonas/administração & dosagem , Quinazolinonas/farmacologia
10.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
11.
Carbohydr Res ; 478: 10-17, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039450

RESUMO

A series of novel tricyclic quinazolinone-iminosugars 1 (a-c) were synthesized from the benzyl protected sugars through three steps. Firstly, the benzyl protected sugar (aldehyde) 5 reacted with o-aminobenzamide by the iodine-induced oxidative condensation to afford the corresponding aldo-quizanolinone 6. Secondly, through the intramolecular cyclization of the unprotected OH and the amide NH in 6, the tricyclic compounds 7 and 8 were constructed by the key Mitsunobu reaction. Finally, removal of the benzyl group gave the target tricyclic quinazolinone-iminosugars 1. The protocol was effective for the preparation of the tricyclic iminosugars in satisfactory yield. Interestingly, an unusual C-2 epimerization was observed with d-mannose and d-ribose compounds under the conditions of the Mitsunobu reaction that generated the products having the trans configuration at the C-2 and C-3 positions. Unfortunately, such tricyclic quinazolinone-iminosugars showed no inhibitory effects on the tested five glycosidases.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/farmacologia , Quinazolinonas/farmacologia , Aspergillus niger/enzimologia , Canavalia/enzimologia , Configuração de Carboidratos , Café/enzimologia , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Glicosídeo Hidrolases/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/química , Prunus dulcis/enzimologia , Quinazolinonas/síntese química , Quinazolinonas/química
12.
Eur J Med Chem ; 172: 26-35, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30939351

RESUMO

Nowadays, due to spreading antibiotic resistance among clinically relevant pathogens, the requirement of novel therapeutic approaches is felt more than ever. One of the alternative strategies is anti-virulence therapy without affecting bacterial growth or viability. In Pseudomonas aeruginosa, an opportunistic human pathogen that exhibits intrinsic multi-drug resistance, both virulence factors' production and biofilm formation depends on its quorum sensing (QS) network. Therefore, targeting the key proteins involved in QS system is an attractive method to overcome P. aeruginosa pathogenicity and resistance. The transcriptional regulator PqsR, also called MvfR, is one of these major proteins which employs 3,4-dihydroxy-2-heptylquinoline (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signaling molecules. Reviewing the advances in development of small molecules inhibit this protein, assist to open a new window to smart molecule design that may revolutionize treatment of P. aeruginosa infections.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , Quinazolinonas/farmacologia , Quinolonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Quinolonas/síntese química , Quinolonas/química , Percepção de Quorum/efeitos dos fármacos , Transativadores
13.
Chem Biol Interact ; 307: 63-72, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009640

RESUMO

This study is aimed to investigate whether Mabuterol (Mab) inhibits proliferation of airway smooth muscle cells (ASMCs) induced by platelet-derived growth factor BB (PDGF-BB) and how far it is related to mitochondrial fission/fusion and intracellular calcium if it comes into play. To explore the mechanism of Mab's antagonizing the proliferation, Mdivi-1, DRP1 inhibitor, which has an inhibitory effect on mitochondrial fission, is used to compare with Mab. Cell viability was measured by either MTT or CCK-8. The inhibitory effect of Mab on S phase of ASM cell cycle induced by PDGF-BB was analyzed by flow cytometry (FCM). Fluo-3/AM, Ca2+ fluorescent probe, was used to detect Ca2+ fluorescence intensity by inverted microscope and flow cytometry. The gene expression of Drp-1 and Mfn-2 was observed with Real time PCR and the proteins of Drp-1, Mfn-2, PCNA and cyclin D1 were assessed by Western Blot. Mab and Mdivi-1 both suppressed the proliferation induced by PDGF-BB. The results from inverted microscope and flow cytometry showed that Mab inhibited [Ca2+]i in rat ASMCs induced by PDGF-BB. Cell cycle concept map illustrated that Mab significantly controlled the S phase of ASM cell cycle induced by PDGF-BB. As a consequence, Real time PCR and Western blot revealed the fact that Mab decreased the expression of Drp-1 mRNA and protein, and promoted the expression of Mfn-2 mRNA and protein. These findings suggested that Mab placed restrictions on the proliferation of rat ASMCs induced by PDGF-BB and the mechanism might be associated with the intracellular calcium inhibited and the mitochondrial fission/fusion regulated by Mab.


Assuntos
Becaplermina/farmacologia , Cálcio/metabolismo , Proliferação de Células/efeitos dos fármacos , Clembuterol/análogos & derivados , Dinâmica Mitocondrial/efeitos dos fármacos , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células Cultivadas , Clembuterol/farmacologia , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Quinazolinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
14.
Eur J Med Chem ; 173: 185-202, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31003060

RESUMO

A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Quinazolinonas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinazolinonas/química , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
15.
Chem Biol Interact ; 304: 173-185, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30894316

RESUMO

The imbalance between mitochondrial fusion and fission has been implicated in cerebral ischemia and several neurodegenerative diseases. However, the role of mitochondrial fission in traumatic brain injury (TBI) remains poorly understood. Mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), which is highly expressed in the nervous system. In the present study, we investigated the changes in Drp1 expression in the ipsilateral hippocampus of rats after TBI and the effects of Mdivi-1 (a selective inhibitor of Drp1) as a post-insult treatment for TBI. Our findings showed that the protein levels of Drp1 were increased at 6 h and peaked at 12 h post-TBI, but we did not observe Drp1 phosphorylation at Ser616, Ser637, Ser40 or Ser44 during this process. We examined the effect of Mdivi-1 on trauma-induced brain damage in both vitro and vivo. In cells, Mdivi-1 significantly attenuated H2O2-induced mitochondrial membrane potential (MMP) dissipation in PC-12 cells. Three days of Mdivi-1 treatment significantly reduced the cortical lesion volume, blood-brain barrier permeability, brain edema and oxidative stress. Mdivi-1 reduced activated caspase-3 release in the cortical border zone and hippocampal dentate gyrus three days after TBI. Furthermore, treatment with Mdivi-1 for 4 weeks rescued neurogenesis in DG and attenuated hippocampal atrophy. Regarding behavioral outcomes, Mdivi-1-treated TBI rats showed a significant improvement in water maze acquisition and retention compared with the saline-treated TBI rats. Moreover, Mdivi-1 treatment reduced anxiety-like behavior in an open-field test. Our results support the notion that Mdivi-1 provides brain protection and improves the behavioral performance in TBI rats.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/psicologia , Dinaminas/antagonistas & inibidores , Quinazolinonas/farmacologia , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Células Cultivadas , Dinaminas/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
16.
Oncol Rep ; 41(5): 3127-3136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896840

RESUMO

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Nitrocompostos/farmacologia , Estirenos/farmacologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Concentração Inibidora 50 , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Nitrocompostos/química , Nitrocompostos/uso terapêutico , Cultura Primária de Células , Prognóstico , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade , Estirenos/química , Estirenos/uso terapêutico
17.
J Chin Med Assoc ; 82(2): 92-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30839497

RESUMO

BACKGROUND: Halofuginone, which is the main active ingredient of Dichroa fabrifuga, was used to inhibit the synthesis of type I collagen and played increasingly important roles in tumor therapy. This study aims to investigate the protective effects of halofuginone on human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and oxidative stress. METHODS: Propidium iodide and Annexin-V double staining assay was used to measure the apoptosis. Cell viability assay, the measurements of reactive oxygen species (ROS) parameters malondialdehyde and superoxide dismutase, western-blot assays, and quantitative PCR were used to elucidate the effects and mechanisms of halofuginone in protecting H2O2-induced injury. RESULTS: The results showed that halofuginone counteracted H2O2-induced cell viability decline and PCNA downregulation. Furthermore, halofuginone decreased ROS levels and protected HUVECs from H2O2-induced apoptosis. In detail, it showed that H2O2 induced a transient activation of Mitogen-activated protein kinases members ERK1/2 and p38, whereas induced a sustained activation of c-Jun N-terminal kinase (JNK), which play dominant roles in triggering apoptosis. Inhibition of JNK activation also inhibited H2O2-mediated apoptosis. Finally, it was shown that halofuginone upregulated VEGF expressions, which functioned by inhibiting sustained JNK activation, thus protecting HUVECs. CONCLUSION: Halofuginone has powerful effects in protecting HUVECs from H2O2-induced apoptosis, via upregulating VEGF and inhibiting overactivated JNK phosphorylation. Halofuginone might be a promising preventive drug for cardiovascular diseases.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/análise
18.
J Enzyme Inhib Med Chem ; 34(1): 672-683, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30821525

RESUMO

Some new 3H-quinazolin-4-one derivatives were synthesised and screened for anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities. Compound 15d was more potent in reducing the cell viabilities of HT-29 and SW620 cells lines to 38%, 36.7%, compared to 5-FU which demonstrated cell viabilities of 65.9 and 42.7% respectively. The IC50 values of 15d were ∼20 µg/ml. Assessment of apoptotic activity revealed that 15d decreased the cell viability by down regulating Bcl2 and BclxL. Moreover, compounds, 8j, 8d/15a/15e, 5b, and 8f displayed lowered IC50 values than oleanolic acid against proinflammatory isoforms of hGV, hG-X, NmPLA2, and AmPLA2. In addition, 8d, 8h, 8j, 15a, 15b, 15e, and 15f showed better anti-α-amylase than quercetin, whereas 8g, 8h, and 8i showed higher anti-α-glucosidase activity than allopurinol. Thus, these compounds can be considered as potential antidiabetic agents. Finally, none of the compounds showed higher antiproteases or xanthine oxidase activities than the used reference drugs.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Peptídeo Hidrolases/metabolismo , Fosfolipases/antagonistas & inibidores , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células HT29 , Humanos , Síndrome Metabólica/metabolismo , Estrutura Molecular , Fosfolipases/metabolismo , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Eur J Med Chem ; 170: 157-172, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884322

RESUMO

Emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Discovery of new antibacterial agents with new mode of action remains a high priority universally. 4(3H)-quinazolinone, a fused nitrogen heterocyclic compound has emerged as a biologically privileged structure, possessing a wide range of biological properties viz. anticancer, antibacterial, antitubercular, antifungal, anti-HIV, anticonvulsant, anti-inflammatory and analgesic activities. Promising antibacterial properties of quinazolinones have enthused the medicinal chemists to explore and develop this fused heterocyclic system for new antibacterial agents. Utilization of quinazolinone core for the design and synthesis of new antibacterial agents has recently gained momentum. This review aims to provide an overview of the structures and antibacterial activity of various 4(3H)-quinazolinone derivatives covering various aspects of in vitro and in vivo pharmacological activities and structure activity relationships (SARs).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Antibacterianos/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Quinazolinonas/uso terapêutico , Relação Estrutura-Atividade
20.
Molecules ; 24(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717179

RESUMO

New quinazolinone derivatives of the marine-derived alkaloids fiscalin B (3) and fumiquinazoline G (1), with neuroprotective and antitumor effects, were synthesized. Eleven quinazolinone-containing indole alkaloids were synthesized, proceeding the anti analogs via a one-pot method, and the syn analogs by the Mazurkiewicz-Ganesan approach. The neuroprotection capacity of these compounds on the rotenone-damage human neuroblastoma cell SH-SY5y was evaluated using the MTT assay. Compounds 1, 3, 5, and 7 showed more than 25% protection. The antitumor activity was investigated using the sulforhodamine B assay and some compounds were tested on the non-malignant MCF-12A cells. Fumiquinazoline G (1) was the most potent compound, with GI50 values lower than 20 µM. Compounds 5, 7, and 11 were more active in all tumor cell lines when compared to their enantiomers. Compounds 5, 7, 10, and 11 had very little effect in the viability of the non-malignant cells. Differences between enantiomeric pairs were also noted as being essential for these activities the S-configuration at C-4. These results reinforce the previously described activities of the fiscalin B (3) as substance P inhibitor and fumiquinazoline G (1) as antitumor agent showing potential as lead compounds for the development of drugs for treatment of neurodegenerative disorders and cancer, respectively.


Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Fármacos Neuroprotetores/síntese química , Peptidomiméticos/síntese química , Quinazolinonas/síntese química , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Peptidomiméticos/farmacologia , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
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