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1.
J Agric Food Chem ; 67(42): 11598-11606, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31560195

RESUMO

A total of 22 quinazoline thioether derivatives incorporating a 1,2,4-triazolo[4,3-a]pyridine moiety were designed, synthesized, and evaluated as antimicrobial agents in agriculture. Among these compounds, the chemical structure of compound 6l was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results revealed that some of the compounds possessed noticeable in vitro antibacterial activities against the tested phytopathogenic bacteria. For example, compounds 6b and 6g had EC50 values as low as 10.0 and 24.7 µg/mL against Xanthomonas axonopodis pv. citri (Xac), respectively, which were significantly better than that of the commercial agrobactericide bismerthiazol (56.9 µg/mL). Particularly, compound 6b was also found to be capable of suppressing the pathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo) approximately 12-fold more potent than control bismerthiazol, in terms of their EC50 values (7.2 versus 89.8 µg/mL). Importantly, the most active compound 6b turned out to be one with the highest hydrophilicity and the lowest molecular weight within the series. In vivo bioassays further showed the application prospect of 6b as a promising plant bactericide for controlling Xoo. Additionally, in vitro antifungal activities of these compounds were also evaluated at the concentration of 50 µg/mL. Overall, the present study demonstrated the potential of 1,2,4-triazolo[4,3-a]pyridine-bearing quinazoline thioether derivatives as efficient agricultural antibacterial agents for crop protection.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Agroquímicos/química , Agroquímicos/farmacologia , Antibacterianos/síntese química , Desenho de Drogas , Piridinas/química , Relação Estrutura-Atividade , Xanthomonas/efeitos dos fármacos
2.
J Agric Food Chem ; 67(40): 11005-11017, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31532657

RESUMO

The limited number of agrochemicals targeting plant bacterial diseases has driven us to develop highly efficient, low-cost, and versatile antibacterial alternatives. Herein, a novel type of simple furan-functionalized quinazolin-4-amines was systematically fabricated and screened for their antibacterial activity. Bioassay results revealed that compounds C1 and E4 could substantially block the growth of two frequently mentioned pathogens Xanthomonas oryzae pv oryzae and X. axonopodis pv citri in vitro, displaying appreciable EC50 values of 7.13 and 10.3 mg/L, respectively. This effect was prominently improved by comparing those of mainly used agrochemicals. An in vivo experiment against bacterial blight further illustrated their viable applications as antimicrobial ingredients. Quantitative proteomics demonstrated that C1 possessed a remarkable ability to manipulate the upregulation and downregulation of expressed proteins, which probably involved d-glucose and biotin metabolic pathways. This finding was substantially verified by parallel reaction monitoring analysis. Scanning electron microscopy images and fluorescence spectra also indicated that the designed compounds had versatile capacities for destroying the integrity of bacteria. Given these remarkable characteristics, furan-functionalized quinazoline hybrids can serve as a viable platform for developing innovative antibiotic alternatives against bacterial infections.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Furanos/farmacologia , Quinazolinas/farmacologia , Xanthomonas/efeitos dos fármacos , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Furanos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Doenças das Plantas/microbiologia , Proteômica , Quinazolinas/química , Relação Estrutura-Atividade , Xanthomonas/genética , Xanthomonas/crescimento & desenvolvimento , Xanthomonas/metabolismo
3.
J Enzyme Inhib Med Chem ; 34(1): 1668-1677, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530043

RESUMO

Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , 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 , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466233

RESUMO

Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-3C, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues. Here, we investigated the cytotoxic mechanism of salt 1-3C compared to its analogue, salt 1-8C, with an extended side carbon chain. Live cell imaging demonstrated that salt 1-3C, but not 1-8C, is rapidly incorporated into mitochondria, correlating with increased cytotoxicity of salt 1-3C. The accumulation in mitochondria led to their fragmentation and loss of function, accompanied by increased autophagy/mitophagy. Salt 1-3C preferentially activated AMP-activated kinase and inhibited mammalian target of rapamycin (mTOR) signaling pathways, sensors of cellular metabolism, but did not induce apoptosis. These data indicate that salt 1-3C cytotoxicity involves mitochondrial perturbation and disintegration, and such compounds are promising candidates for targeting mitochondria as a weak spot of cancer.


Assuntos
Antineoplásicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/química , Carbocianinas/química , Linhagem Celular Tumoral , Humanos , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Compostos de Amônio Quaternário/química , Quinazolinas/química , Serina-Treonina Quinases TOR/metabolismo
5.
Eur J Med Chem ; 181: 111552, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387063

RESUMO

Tyrosine kinase inhibitors (TKIs) have achieved substantial clinical effects for cancer treatment while causing a number of adverse effects. Since hypoxia is an intrinsic difference between solid tumor and healthy tissues, one strategy to overcome the adverse effects of TKIs is to enhance the specificity of anti-tumor activity by selectively targeting hypoxic region of tumors. Herein, we designed and synthesized a series of novel 4-anilinoquinazoline derivatives by introducing 3-nitro-1,2,4-triazole group to the side chain of vandetanib with modification of aniline moiety. Lead compounds, 10a and 10g, exhibited potent inhibitory activity against EGFR and VEGFR-2 kinase. Moreover, these two compounds were shown to enhance anti-proliferative activities on A549 and H446 cells under hypoxic conditions compared to vandetanib and dramatically down-regulate VEGF gene expression. In vivo studies confirmed that 10a and 10g not only inhibited tumor growth in A549 xenografts of BALB/c-nu mice but also significantly reduce toxicity associated with weight loss compared to vandetanib. These results suggest that EGFR/VEGFR-2 dual inhibitors, 10a and 10g, emerged as potential hypoxia-selective anti-tumor drugs with less toxicity for inhibiting in vitro and in vivo models of non-small cell lung cancer cells.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Compostos de Anilina/síntese química , Compostos de Anilina/química , 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 , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
6.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295928

RESUMO

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center.


Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP3A/metabolismo , Enzimas/metabolismo , Oxirredução , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Antineoplásicos/química , Citocromo P-450 CYP3A/química , Relação Dose-Resposta a Droga , Enzimas/química , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Coelhos , Ratos , Proteínas Recombinantes
7.
Nanoscale ; 11(29): 13947-13960, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31305836

RESUMO

Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. These particles were determined to have a diameter of ∼115 nm, with a polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 cells determined through flow cytometry showed a ∼5-fold increase between untargeted and HA-coated particles. Through viability and DNA damage assays, we assessed the potency of the free RTX and HARPs, and found increased DNA damage in cells treated with the RTX-loaded nanoparticles administered concurrently with radiation. In vivo efficacy through tumor growth inhibition was investigated in a syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute toxicity in vivo, and all treatments showed survival benefits for their respective groups compared to controls. HARPs alone slowed tumor growth, although not significantly. Radiation alone and in combination with the HARPs showed significant growth delay. Notably, the combination treatment significantly hindered tumor progression relative to the HARPs highlighting the benefit of this multipronged treatment. These results provide a foundation for loading RTX in a nanoparticle formulation, and establish a combined radiation and drug dosing schedule to determine optimal tumor growth delay and subsequent treatment efficacy.


Assuntos
Antimetabólitos Antineoplásicos/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Quinazolinas/química , Tiofenos/química , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Dano ao DNA/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Radiação Ionizante , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Transplante Heterólogo
8.
Phytomedicine ; 63: 153007, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301537

RESUMO

BACKGROUND: Aerial parts of Peganum harmala Linn is used as a traditional medical herb for treatment of amnesia in Uighur medicine in China. Deoxyvasicine (DVAS) is one of the chief active ingredients in P. harmala, it possesses strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in vitro, but the therapeutic effect and mechanisms on amnesia in vivo are unclear. PURPOSE: The objective of this study was to investigate the improvement effect of DVAS from P. harmala in learning and memory deficits of scopolamine-induced mice and elucidate the underlying mechanisms involved. METHODS: Mice were pretreated with DVAS (5, 15 and 45 mg/kg) and huperzine-A (0.2 mg/kg) by gavage for 7 days, and subsequently were daily intraperitoneally injected with scopolamine (1 mg/kg) to induce learning and memory deficits and behavioral performance was assessed by Morris water maze. To further evaluate the potential mechanisms of DVAS in improving learning and memory capabilities, pathological change, levels of various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation were examined. RESULTS: The results showed that DVAS could alleviate learning and memory deficits in scopolamine-treated mice. DVAS could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities and protein expressions. DVAS could induce brain-derived neurotrophic factor and protect hippocampal pyramidal cells against neuronal damage. DVAS also enhanced antioxidant defense via increasing the antioxidant enzyme level and activity of glutathione peroxidase, and anti-inflammatory function through suppressing tumor necrosis factor-α. Additionally, DVAS could regulate the neurotransmitters by elevating acetylcholine, 5-hydroxytryptamine, γ-aminobutyric acid and reducing 5-hydroxyindole-3-acetic acid and glutamic acid. CONCLUSION: Results illustrated that DVAS may be a promising candidate compound against amnesia via restoration of cholinergic function, regulating neurotransmitters, attenuating neuroinflammation and oxidative stress.


Assuntos
Alcaloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Quinazolinas/farmacologia , Acetilcolina/metabolismo , Amnésia/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peganum/química , Escopolamina/toxicidade , Sesquiterpenos/farmacologia
9.
Int J Mol Sci ; 20(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269745

RESUMO

Pancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation. In this study, we aimed at comparing the in vitro capacities of the HDACi SAHA and CUDC-101 to increase radiosensitivity of human pancreatic tumor cell lines. Therefore, three pancreatic cancer cell lines (Su.86.86, MIA Paca-2, T3M-4) were treated with SAHA (1.5-5 µM) or CUDC-101 (0.25-3 µM) and after 24 h irradiated. Cell proliferation, clonogenic survival and apoptosis was determined. Additionally, cell lysates were investigated for the expression of apoptosis-related proteins. CUDC-101 and SAHA increased the radiation sensitivity of pancreatic tumor cell lines in a dose-dependent manner. This was evidenced by cell proliferation and clonogenic survival. Furthermore, enhanced radiation sensitivity after CUDC-101 or SAHA treatment was confirmed for Su.86.86 and T3M-4 cells in a 3-D microtissue approach. Increased amounts of subG1 cells and diminished full length PARP-1 suggest increased radiation-induced apoptosis after SAHA or CUDC-101 treatment. The comparison of both inhibitors in these assays manifested CUDC-101 as more potent radiosensitizer than SAHA. In line, western blot quantification of the apoptosis-inhibitory proteins XIAP and survivin showed a stronger down-regulation in response to CUDC-101 treatment than after SAHA application. These proteins may contribute to the synergy between HDAC inhibition and radiation response. In conclusion, these preclinical results suggest that treatment with the HDAC inhibitors CUDC-101 or SAHA can enhance radiation-induced cytotoxicity in human pancreatic cells. However, comparison of both inhibitors identified the multi target inhibitor CUDC-101 as more potent radiosensitizer than the HDAC inhibitor SAHA.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Quinazolinas/farmacologia , Radiossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia
10.
Biomed Pharmacother ; 117: 109165, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261030

RESUMO

Gastric cancer (GC) is one of the most lethal malignancies. Chemoresistance and metastasis are the main cause of treatment failure. Cancer stem cells (CSCs) have been proven to be essential for cancer metastasis and chemoresistance. PKCδ (protein kinase C-δ), a novel member of PKC family, has been validated as a synthetic lethal target in multiple cancers, and contributes to tyrosine kinase inhibitors (TKI) resistance in EGFR-mutant NSCLC (non-small cell lung cancer) patients. However, its role in GC is unclear. Here, we systematically investigate its role in GC, especially in regulating GC stem cell-like properties. We found that PKCδ positively regulated the metastasis, chemoresistance, and stem cell-like characteristics of GC cells, and its inhibitor sotrastaurin could rescue the above effects mediated by PKCδ. Importantly, sotrastaurin could also weaken metastasis, chemoresistance, and stem cell-like characteristics of adriamycin-resistant GC cells via PKCδ suppression, indicating sotrastaurin is an ideal candidate for combinational therapy to overcome chemoresistance for GC.


Assuntos
Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Proteína Quinase C-delta/metabolismo , Pirróis/farmacologia , Quinazolinas/farmacologia , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Metástase Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos
11.
Anticancer Res ; 39(7): 3571-3578, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262881

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective, cell-death-inducing agent with little toxicity to normal cells. However, various human cancers and cancer cell lines have been reported to be resistant to TRAIL. Molecular clarification of resistance mechanism is needed. MATERIALS AND METHODS: Compound screening, proliferation assays, western blotting, and flow cytometry were used to examine the sensitizer activity of methyl transferase inhibitor BIX-01294 in combination with TRAIL, in hepatocellular carcinoma (HCC) cells. RNA sequencing analysis and single guide (sg)RNA-mediated gene deletion were used to investigate the role of survivin in sensitization. RESULTS: In HCC cells, BIX-01294 enhanced TRAIL sensitivity by reducing survivin expression at the RNA level. Small interference RNA-mediated gene knockdown demonstrated the mechanism of sensitization to be via the reduction of survivin. CONCLUSION: Euchromatin histone methyltransferase 2 (EHMT2) inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human HCC.


Assuntos
Azepinas/farmacologia , Carcinoma Hepatocelular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quinazolinas/farmacologia , Survivina/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Survivina/genética
12.
Cell Prolif ; 52(5): e12657, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264311

RESUMO

OBJECTIVES: A high rate of chromosome aneuploidy is exhibited in in vitro fertilization (IVF)-derived embryos. Our previous experiments suggested that reactive oxygen species (ROS) can activate Mad2, a key protein in the spindle assembly checkpoint (SAC), and delay the first mitotic, providing time to prevent the formation of embryonic aneuploidy. We aimed to determine whether mitotic kinase Aurora B was involved in the SAC function to prevent aneuploidy in IVF-derived embryos. MATERIALS AND METHODS: We analysed aneuploidy formation and repair during embryo pre-implantation via 4',6-diamidino-2-phenylindole (DAPI) staining and karyotype analysis. We assessed Aurora B activation by immunofluorescence and investigated the effect of Aurora B inhibition on embryo injury-related variables, such as embryonic development, ROS levels, mitochondrial membrane potential and γH2AX-positive expression. RESULTS: We observed the expression and phosphorylation of Thr232 in Aurora B in oxidative stress-induced zygotes. Moreover, inhibition of Aurora B caused chromosome mis-segregation, abnormal spindle structures, abnormal chromosome number and reduced expression of Mad2 in IVF embryos. Our results suggest that Aurora B causes mitotic arrest and participates in SAC via Mad2 and H3S10P, which is required for self-correction of aneuploidies. CONCLUSIONS: We demonstrate here that oxidative stress-induced DNA damage triggers Aurora B-mediated activation of SAC, which prevents aneuploidy at the first mitotic cleavage in early mouse IVF embryos.


Assuntos
Aurora Quinase B/metabolismo , Proteínas Mad2/metabolismo , Aneuploidia , Animais , Aurora Quinase B/antagonistas & inibidores , Segregação de Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Feminino , Peróxido de Hidrogênio/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitose , Organofosfatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Quinazolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Zigoto/metabolismo
13.
J Agric Food Chem ; 67(33): 9254-9264, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31356740

RESUMO

In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.


Assuntos
Benzoxazinas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Herbicidas/química , Herbicidas/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Protoporfirinogênio Oxidase/antagonistas & inibidores , Quinazolinas/química , Benzoxazinas/farmacologia , Desenho de Drogas , Cinética , Proteínas de Plantas/química , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Protoporfirinogênio Oxidase/química , Relação Quantitativa Estrutura-Atividade , Quinazolinas/farmacologia , Tabaco/efeitos dos fármacos , Tabaco/enzimologia , Controle de Plantas Daninhas
14.
Eur J Med Chem ; 178: 417-432, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202990

RESUMO

In novel synthetic 28 4-arylamino-6-fluoro quinazoline derivatives, compound 3a displayed the most remarkable inhibitory activities against tumor cells (IC50 values ranging between 0.71 and 2.30 µM) in vitro. Importantly, 3a obviously inhibited the proliferation and metastasis of A549 cells in a zebrafish xenograft model, while also mediated cell apoptosis and G0/G1-phase cell cycle arrest in A549 cells. Interestingly, 3a had excellent fluorescence at 439 nm (λex = 375 nm) in DMSO and at 428 nm (λex = 372 nm) in 0.5% DMSO-phosphate buffer, and the self-fluorescent characteristic revealed 3a itself accumulates in the mitochondria of A549 cells, which suggested the antitumor process of 3a may involve the mitochondrial apoptotic pathway. The hypothesis was verified by the increase of the intracellular reactive oxygen species, the decrease of mitochondrial membrane potential, the release of cytochrome C from the mitochondria into the cytoplasm, and the cascade activation of caspase-9 and caspase-3 when A549 cells were treated with 3a. This work has great implications for further development of anticancer agents that can be enriched in mitochondria and can be tracked in real-time in biological systems due to the ideal fluorescence.


Assuntos
Antineoplásicos/farmacologia , Fluorescência , Mitocôndrias/efeitos dos fármacos , Quinazolinas/farmacologia , Células A549 , 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 , Humanos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Peixe-Zebra
15.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
16.
Int J Mol Med ; 44(2): 437-446, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173177

RESUMO

The abnormal activation of the downstream signaling pathways of epidermal growth factor receptor (EGFR) that are independent of EGFR, contribute to the acquisition of EGFR­tyrosine kinase inhibitor (TKI) resistance in non­small cell lung cancer (NSCLC). The serine/threonine protein kinase casein kinase II (CK2) phosphorylates and modulates several members of the EGFR downstream signaling pathways. Thus, the purpose of the current study was to investigate the effects of the addition of quinalizarin (a specific CK2 inhibitor) to icotinib (an EGFR­TKI) on the proliferation and apoptosis of four NSCLC cell lines and its underlying mechanisms. The human lung adenocarcinoma cell lines HCC827, A549, H1650 and H1975 were employed to represent the EGFR­TKI­sensitive EGFR (EGFR­sensitive) mutation, wild­type EGFR and the EGFR­TKI­resistant EGFR (EGFR­resistant) mutations. The cell viability was determined by the MTT assay. Cell apoptosis was detected by flow cytometry using the Annexin V­enhanced green fluorescent protein Apoptosis Detection kit. The level of proteins in the EGFR downstream pathway was observed using a western blot assay. The results showed that the cells with the EGFR­sensitive mutation (HCC827, EGFR E716­A750del) were more sensitive to icotinib compared with those possessing the EGFR wild­type (A549) and the EGFR­resistant mutations (H1650, EGFR E716­A750del and PTEN lost; H1975, EGFR L858R+T790M). Quinalizarin inhibited proliferation and promoted apoptosis in the cells with the EGFR wild­type and resistant mutations, and the addition of quinalizarin to icotinib partially restored their sensitivity to icotinib. Quinalizarin and/or icotinib increased the apoptotic rates in the EGFR­TKI resistant cells, and the combination of these reduced the level of protein downstream of EGFR, including phosphorylated (p­AKT) and p­(ERK). In conclusion, quinalizarin may partially sensitize cells to icotinib by inhibiting proliferation and promoting apoptosis mediated by AKT and ERK in EGFR­TKI resistant NSCLC cell lines.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Éteres de Coroa/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/farmacologia
17.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197089

RESUMO

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways.


Assuntos
Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptor PAR-1/metabolismo , Transdução de Sinais , Trombina/farmacologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Quinazolinas/farmacologia , Receptor PAR-1/agonistas , Receptor PAR-1/antagonistas & inibidores , Proteínas de Transporte Vesicular/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo
18.
Expert Rev Clin Pharmacol ; 12(8): 713-721, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177854

RESUMO

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect. Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed. Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Benzofuranos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Quinazolinas/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacologia , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
19.
Int J Clin Pharmacol Ther ; 57(9): 450-457, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31232280

RESUMO

OBJECTIVE: Letermovir is an inhibitor of the terminase complex of cytomegalovirus (CMV) used as prophylactic therapy in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. As the combination oral contraceptive (COC) levonorgestrel/ethinyl estradiol (LNG/EE) may be coadministered in this target transplant population, the effects of letermovir on the pharmacokinetics (PK) of LNG and EE were investigated. MATERIALS AND METHODS: This was a phase I, open-label, fixed-sequence, two-period study conducted in healthy women (18 - 65 years old) of non-childbearing potential (protocol number: MK-8228 035). On day 1 of period 1, participants received a single dose of COC (LNG 0.15 mg/EE 0.03 mg). Following a 7-day washout, oral letermovir 480 mg was administered once-daily on days 1 - 12 of period 2, with a single dose of COC coadministered on day 8. Blood samples were collected to determine LNG and EE PK, and safety was assessed. RESULTS: The AUC0-∞ geometric mean ratios (90% confidence intervals) for COC + letermovir/COC alone were 1.36 (1.30, 1.43) for LNG and 1.42 (1.32, 1.52) for EE, indicating that letermovir coadministration increased COC exposure. Coadministration had no clinically-meaningful effect on Cmax, tmax, or apparent terminal T1/2 for either LNG or EE. All treatments were generally well tolerated. CONCLUSION: Letermovir coadministration with COC resulted in an increase in LNG and EE exposure in healthy adult women; however, levels were within the established safety margins. There was no decrease in LNG or EE exposure with no apparent risk of contraceptive failure on coadministration of letermovir and COC.
.


Assuntos
Acetatos/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Quinazolinas/farmacologia , Adolescente , Adulto , Idoso , Interações de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
20.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(2): 178-182, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31250613

RESUMO

OBJECTIVE: To investigate the effects of rutaecarpine on high glucose-induced Alzheimer's disease-like pathological and cognitive dysfunction and its mechanism in rats. METHODS: Adult male SD rats were randomly divided into three groups (n=20): control group, high glucose group and rutaecarpine group. Rats in the control group were fed with conventional feed and tap water. The rats in the high glucose group were fed with conventional feed and 20% sucrose water. The rutaecarpine group was fed with fodder contain 0.01% rutaecarpine and 20% sucrose water. Morris water maze test was used to detect learning and memory and cognitive function of three groups rats after 24 weeks of feeding. Western blot analysis was used to detect tau protein at Thr205 and Ser214 sites in each group. Phosphorylation levels of GSK-3ß in serine 9 site (S9-GSK-3ß) and PP2A at cycline 307 site (Y307-PP2AC) were also detected. Immunohistochemistry further confirmed tau protein at Thr205 site in each group both in hippocampus and cortex. RESULTS: Compared with the control group, Morris water maze results showed that the latency of finding the hidden platform of the rats in high glucose group was increased significantly and the number of crossing platforms and the target quadrant residence time were significantly decreased (all P<0.05). Immunohistochemistry showed that the phosphorylation level of tau protein at Thr205 site was significantly increased in the high glucose group compared with the control group, and the phosphorylation level of tau protein at Thr205 site in the rutaecarpine group was higher than that in the high glucose group. Western blot analysis showed that the phosphorylation level of tau protein in the high glucose group was significantly increased at Thr205 and Ser214 site compared with the control group, but the phosphorylation level of pS9-GSK-3ß was significantly decreased (all P <0.05). Compared with the high glucose group, the latency of finding the hidden platform of the rats in rutaecarpine group was significantly decreased, and the number of crossing platforms and the target quadrant residence time were significantly increased (both P<0.05). Compared with the high glucose group, the phosphorylation levels of tau protein at Thr205 and Ser214 sites showed a significant decrease, but the phosphorylation level of pS9-GSK-3ß was significantly increased (all P<0.05). CONCLUSION: Rutaecarpine can alleviate AD-like cognitive dysfunction induced by high glucose, possibly by enhancing pS9-GSK-3ß phosphorylation, down-regulating GSK-3ß activity, and thus reducing hyperphosphorylation of tau-associated sites.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/química , Alcaloides Indólicos/farmacologia , Quinazolinas/farmacologia , Proteínas tau/química , Doença de Alzheimer/induzido quimicamente , Animais , Disfunção Cognitiva/induzido quimicamente , Glucose , Masculino , Aprendizagem em Labirinto , Fosforilação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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