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1.
J Agric Food Chem ; 67(39): 10844-10852, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525997

RESUMO

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Isoindóis/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Pirazóis/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Isoindóis/química , Cinética , Estrutura Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Pirazóis/química , Relação Estrutura-Atividade
2.
J Agric Food Chem ; 67(40): 11035-11043, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31517486

RESUMO

Ca2+-binding proteins (CaBPs) are widely distributed as Ca2+ sensor relay proteins that regulate various cellular processes, including Ca2+ homeostasis. Diamide insecticides such as cyantraniliprole kill insects by disrupting the Ca2+ homeostasis in muscle cells. However, less attention has been paid to the roles of CaBPs in response to insecticides. In this study, two CaBP genes (BtCaBP1 and BtCaBP2) were identified in the whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), and their functions in response to cyantraniliprole were investigated. After expression of BtCaBP1 and BtCaBP2 in vitro, the results of Ca2+ imaging and cytotoxicity assay revealed that the overexpression of each of the BtCaBPs stabilized Ca2+ concentration in the cytoplasm after exposure to cyantraniliprole and decreased the toxicity of cyantraniliprole against Sf9 cells. However, the knockdown of BtCaBP1 or BtCaBP2 in vivo significantly increased the toxicity of cyantraniliprole to B. tabaci. Taken together, these results provide evidence that BtCaBP1 and BtCaBP2 play a role in response to cyantraniliprole exposure through stabilization of Ca2+ concentration in whiteflies.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Clonagem Molecular , Hemípteros/efeitos dos fármacos , Hemípteros/genética , Proteínas de Insetos/metabolismo , Inseticidas/farmacologia , Pirazóis/farmacologia , ortoaminobenzoatos/farmacologia , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Hemípteros/classificação , Hemípteros/metabolismo , Proteínas de Insetos/genética , Filogenia
3.
Pestic Biochem Physiol ; 158: 18-24, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378355

RESUMO

Outbreaks of bitter rot were observed in three commercial apple orchards in Illinois despite best management efforts during the 2018 production season. Three isolates from symptomatic fruit from these orchards and two isolates from an orchard in South Carolina were identified to the species level using morphological tools and calmodulin, glyceraldehyde-3-phosphate dehydrogenase, and beta-tubulin gene sequences. The isolates from Illinois were identified as Colletotrichum siamense of the Colletotrichum gloeosporioides species complex and the ones from South Carolina as Colletotrichum fioriniae and Colletotrichum fructicola of the Colletotrichum acutatum and the C. gloeosporioides species complex, respectively. Two of the three C. siamense isolates from Illinois were resistant to azoxystrobin and thiophanate-methyl as determined in mycelial growth tests in vitro. EC50 values were >100 µg/ml for both fungicides. One isolate was only resistant to azoxystrobin. None of the isolates from South Carolina was resistant to either of the two compounds. All five isolates were sensitive to fludioxonil (EC50 values <0.1 µg/ml), propiconazole (EC50 values ranged from 0.15 to 0.36 µg/ml), and benzovindiflupyr (EC50 values ranged from <0.1 to 0.33 µg/ml). Resistance in C. siamense to azoxystrobin and thiophanate-methyl was confirmed in detached fruit studies using apples treated with label rates of registered product. Resistance to thiophanate-methyl in C. siamense was based on E198A mutation in b-tubulin gene, whereas resistance to azoxystrobin was based on G143A in cytochrome b (CYTB). One isolate resistant to azoxystrobin possessed no amino acid variation in CYTB. This study shows that quinone outside inhibitor fungicide resistance in Colletotrichum from apple has emerged and is being selected for in Illinois apple orchards by current spray strategies. Resistance monitoring may alert growers to potential threats, but the employment of molecular tools based on current knowledge of resistance mechanisms will provide incomplete results.


Assuntos
Colletotrichum/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Malus/microbiologia , Benzimidazóis/farmacologia , Colletotrichum/genética , Citocromos b/genética , Citocromos b/metabolismo , Dioxóis/farmacologia , Farmacorresistência Fúngica/genética , Frutas/microbiologia , Malus/genética , Norbornanos/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Estrobilurinas/farmacologia , Tiofanato/farmacologia , Triazóis/farmacologia
4.
Pestic Biochem Physiol ; 158: 32-39, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378358

RESUMO

Mutations in the GABA-gated chloride channel are associated with resistance to cyclodiene organochlorine and phenyl pyrazole insecticides. The best characterised of these is A301S, which was initially identified in a Dieldrin resistant strain of Drosophila melanogaster. The orthologous mutation has been found in a variety of different crop pests including the diamond back moth Plutella xylostella. However, the contribution of this mutation to resistance in this species remains unclear. We have used the CRISPR/Cas9 system in order to edit Plutella xylostella PxGABARalpha1 to Serine at the 301 orthologous position (282 in PxGABARalpha1) in an insecticide sensitive strain isolated from Vero Beach (VB) USA. In this edited line, no high level of resistance is conferred to Dieldrin, Endosulfan or Fipronil, rather only a subtle shift in sensitivity which could not confer commercially important resistance. We conclude that the high level of commercial resistance to cyclodiene organochlorine and phenyl pyrazole insecticides observed in some field isolates of Plutella xylostella cannot arise from A282S in PxGABARalpha1 alone.


Assuntos
Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Animais , Sistemas CRISPR-Cas/genética , Dieldrin/farmacologia , Endossulfano/farmacologia , Resistência a Inseticidas/genética , Mariposas/genética , Mutação/genética , Pirazóis/farmacologia , Receptores de GABA-A/genética
5.
Plant Dis ; 103(10): 2498-2504, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31453746

RESUMO

Downy mildew is a yield-limiting disease of sunflower, caused by the pathogen Plasmopara halstedii. Zoospore infection of root tissue shortly after planting results in systemic infection, causing postemergence damping off or severe stunting and head sterility. Although fungicide-applied seed treatments can be an effective management tool, the pathogen is resistant to phenylamide fungicides in many growing regions, and other available fungicides have limited efficacy. Oxathiapiprolin, the first member of the piperidinyl thiazole isoxazoline fungicides, was evaluated for efficacy on downy mildew in field trials conducted from 2011 to 2015 in North Dakota. Throughout the course of the study, the rate range was narrowed from active ingredient (a.i.) at 0.45 to 116.0 µg a.i. seed-1 to an optimal effective rate of 9.37 to 18.75 µg a.i. seed-1. Within that optimal range, the downy mildew incidence of sunflower planted with oxathiapiprolin-treated seed was significantly lower than the incidence in the nontreated sunflower in all 11 trials with disease pressure. Additionally, downy mildew incidence of sunflower planted with oxathiapiprolin-treated seed was significantly lower than sunflower planted with competitive commercially available fungicide-treated seed in 10 of those 11 trials. The use of oxathiapiprolin by sunflower growers is likely to reduce disease incidence and subsequent yield loss to downy mildew.


Assuntos
Helianthus , Hidrocarbonetos Fluorados , Oomicetos , Doenças das Plantas , Pirazóis , Antiparasitários/farmacologia , Helianthus/parasitologia , Hidrocarbonetos Fluorados/farmacologia , North Dakota , Oomicetos/efeitos dos fármacos , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Pirazóis/farmacologia , Sementes/química
6.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
7.
J Enzyme Inhib Med Chem ; 34(1): 1314-1320, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31307243

RESUMO

BRAF belongs to the upstream portion of the MAPK pathway, which is involved in cell proliferation and survival. When mutations occur in BRAF, downstream MEK and ERK are phosphorylated irrespective of RAS, resulting in melanoma-like cancer. Over the years, small molecules targeting BRAFV600E have been discovered to be very effective melanoma drugs, but they are known to cause the BRAF paradox. Recently, it was shown that this paradox is caused by the heterodimer phenomenon of BRAF/CRAF. Here, we suggest one method by which paradoxical activation can be avoided by selectively inhibiting BRAFV600E and CRAF but not wild-type BRAF. From previous report of N-(3-(3-alkyl-1H-pyrazol-5-yl) phenyl) aryl amide as a selective inhibitor of BRAFV600E and CRAF, we present compounds that offer enhanced selectivity and efficacy with the aid of molecular modelling.


Assuntos
Projeto Auxiliado por Computador , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
8.
Cell Physiol Biochem ; 53(1): 186-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278696

RESUMO

BACKGROUND/AIMS: Estrogen could play a key role in the mechanisms underlying sex-related disparity in the incidence of thrombotic events. We investigated whether estrogen receptors (ERs) were expressed in human red blood cells (RBCs), and if they affected cell signaling of erythrocyte constitutive isoform of endothelial NO-synthase (eNOS) and nitric oxide (NO) release. METHODS: RBCs from 29 non-smoker volunteers (15 males and 14 females) aged between 20 and 40 years were analyzed by cytometry and western blot. In particular, content and distribution of ER-α and ER-ß, tyrosine kinases and eNOS phosphorylation and NO release were analyzed. RESULTS: We demonstrated that: i) both ER-α and ER-ß were expressed by RBCs; ii) they were both functionally active; and iii) ERs distribution and function were different in males and females. In particular, ERs modulated eNOS phosphorylation and NO release in RBCs from both sexes, but they induced the phosphorylation of specific tyrosine residues of kinases linked to eNOS activation and NO release in the RBCs from females only. CONCLUSION: Collectively, these data suggest that ERs could play a critical role in RBC intracellular signaling. The possible implication of this signaling in sex-linked risk disparity in human cardiovascular diseases, e.g. in thrombotic events, may not be ruled out.


Assuntos
Receptores Estrogênicos/metabolismo , Transdução de Sinais , Adulto , Dronabinol/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
9.
Br J Anaesth ; 123(2): 186-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202564

RESUMO

BACKGROUND: Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model. METHODS: Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss. RESULTS: Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P<0.01]. Controls exhibited total blood loss of 3403 (766) ml, with 100% mortality. Andexanet bolus or bolus plus infusion significantly reduced blood loss to 1264 (205) and 1202 (95) ml, respectively), and increased survival to 100%. Haemodynamic parameters and markers of shock recovered to pre-trauma levels in andexanet-treated animals. CONCLUSION: Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Traumatismo Múltiplo , Pirazóis/farmacologia , Piridonas/farmacologia , Proteínas Recombinantes/farmacologia , Animais , Anticoagulantes/farmacologia , Modelos Animais de Doenças , Masculino , Suínos
10.
Yonsei Med J ; 60(7): 626-632, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250576

RESUMO

PURPOSE: To compare the effect of apixaban and low molecular weight heparin (LMWH) in the prevention and treatment of deep venous thrombosis (DVT) after total knee arthroplasty in older adult patients. MATERIALS AND METHODS: A total of 220 patients (average age of 67.8±6.4 years) undergoing total knee arthroplasty were randomly selected as research subjects and were divided into apixaban and LMWH groups (110 in each group). RESULTS: The incidence of DVT was lower in the apixaban group than in the LMWH group (5.5% vs. 20.0%, p=0.001). Activated partial thromboplastin times (35.2±3.6 sec vs. 33.7±2.2 sec, p=0.010; 37.8±4.6 sec vs. 34.1±3.2 sec, p<0.001; 39.6±5.1 sec vs. 35.7±3.0 sec, p=0.032) and prothrombin times (14.0±1.0 sec vs. 12.8±0.9 sec, p<0.001; 14.5±1.2 sec vs. 13.0±1.1 sec, p<0.001; 15.3±1.4 sec vs. 13.2±1.3 sec, p=0.009) in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were higher than those in the LMWH group. Platelet and fibrinogen levels in the apixaban group were lower than those of the LMWH group. Also, capillary plasma viscosity and erythrocyte aggregation in the apixaban group at 1 week after surgery, 3 weeks after surgery, and the end of treatment were lower than those in the LMWH group. CONCLUSION: Apixaban, which elicits fewer adverse reactions and is safer than LMWH, exhibited better effects in the prevention and treatment of DVT after total knee arthroplasty in older adults.


Assuntos
Anticoagulantes/farmacologia , Artroplastia do Joelho/efeitos adversos , Heparina de Baixo Peso Molecular/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Trombose Venosa/prevenção & controle , Idoso , Feminino , Humanos , Masculino , Fatores de Tempo , Trombose Venosa/etiologia
11.
Eur J Med Chem ; 178: 1-12, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31167153

RESUMO

Indenopyrazole is emerging as one of the most promising and privileged scaffold in medicinal chemistry. This scaffold have been investigated for the development of novel derivatives and hybrids with other moieties and substituents exhibiting a wide range of medicinal properties like antimycobacterial, antipsychotic, antihypertensive, cannabinoid receptor affinity, anti-tumor, antimicrobial, etc. Furthermore, indenopyrazoles function as inhibitors in various mechanistic pathways which has been well established based on its anticancer potential. This review illustrates various synthetic strategies adopted and reveals the extensive significant biological properties of indenopyrazoles. Furthermore, ample scope is available for this scaffold which needs to be explored by medicinal chemists for the development of new potential drug candidates.


Assuntos
Indenos/farmacologia , Pirazóis/farmacologia , Animais , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Humanos , Indenos/síntese química , Pirazóis/síntese química
12.
Eur J Med Chem ; 178: 168-176, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181481

RESUMO

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/síntese química , Esteroides/metabolismo , Fatores de Transcrição/metabolismo
13.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
14.
Eur J Med Chem ; 177: 425-447, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158755

RESUMO

Mutated adenomatous polyposis coli (APC) selectively combining with Asef has been reported to be implicated in promoting colon cancer proliferation, invasion and metastasis in several cancer biotherapy studies. However, there were universally resistance and harsh terms in disrupting APC-Asef interaction in biotherapy. Under the circumstances small-molecule inhibitors as the new APC interface could resolve the problems. In this research, a series of novel dihydropyrazole derivatives containing morpholine as high potent interaction inhibitors between APC and Asef were first synthesized after selection by means of docking simulation and virtual screening. Afterwards they were evaluated interaction inhibition of APC-Asef and pharmacological efficiency both in vitro and in vivo utilizing orthotopic transplantation model with multi-angle of view. Among them, compound 7g exhibited most excellent anti-proliferation activities against HCT116 cells with IC50 of 0.10 ±â€¯0.01 µM than Regorafenib (IC50 = 0.16 ±â€¯0.04 µM). The results favored our rational design intention and provides a new class of small-molecule inhibitors available for the development of colon tumor therapeutics targeting APC-Asef interaction inhibitions.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Antineoplásicos/uso terapêutico , Morfolinas/uso terapêutico , Pirazóis/uso terapêutico , Proteína da Polipose Adenomatosa do Colo/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/farmacologia , Transplante de Neoplasias , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Fatores de Troca de Nucleotídeo Guanina Rho/química , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Relação Estrutura-Atividade , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Molecules ; 24(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035548

RESUMO

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c-j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1 antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.


Assuntos
Desenvolvimento de Medicamentos , Oxigênio/química , Pirazóis/química , Receptor CB1 de Canabinoide/química , Animais , Biomarcadores , Linhagem Celular , Relação Dose-Resposta a Droga , Ligantes , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Especificidade de Órgãos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Relação Estrutura-Atividade
16.
Chem Biodivers ; 16(7): e1900118, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31106521

RESUMO

In continuation of our previous research on the development of novel pyrazole-4-carboxamide with potential antifungal activity, compound SCU2028, namely N-[2-[(3-chlorophenyl)amino]phenyl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide, was synthesized by new method, structurally characterized by IR, HR-ESI-MS, 1 H- and 13 C-NMR spectra and further identified by single-crystal X-ray diffraction. In pot tests, compound SCU2028 showed good in vivo antifungal activity against Rhizoctonia solani (R. solani) and IC50 value of it was 7.48 mg L-1 . In field trials, control efficacy of compound SCU2028 at 200 g.a.i. ha-1 was 42.30 % on the 7th day after the first spraying and 68.10 % on the 14th day after the second spraying, only slightly lower than that of thifluzamide (57.20 % and 71.40 %, respectively). Further in vitro inhibitory activity showed inhibitory ability of compound SCU2028 was 45-fold higher than that of bixafen and molecular docking of compound SCU2028 to SDH predicted its binding orientation in the active site of the target protein SDH. These results suggested that compound SCU2028 was a potential fungicide for control of rice sheath blight.


Assuntos
Antifúngicos/farmacologia , Simulação de Acoplamento Molecular , Pirazóis/farmacologia , Rhizoctonia/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química
17.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052167

RESUMO

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Drogas , Oxigênio/química , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo , Inibidores de Ciclo-Oxigenase 2/síntese química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirazóis/síntese química , Relação Quantitativa Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Med Rep ; 19(6): 5087-5096, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059046

RESUMO

The present study aimed to investigate the inhibitory effects and the mechanisms underlying 17ß­estradiol (E2) effects on triglyceride synthesis and insulin resistance in skeletal muscle tissues and cells. Ovariectomy (OVX) was performed on 6­month­old female rats treated with or without E2. Subsequently, various serum biochemical markers were measured. Additionally, pathological alterations of the uterus, liver and skeletal muscle were analyzed, and the content of triglycerides (TG) in muscle was detected. Differentiated myotubes formed by C2C12 cells were treated with palmitic acid (PA) or pretreated with E2, estrogen receptor (ESR) 1 agonist propylpyrazoletriol (PPT) and ESR2 agonist diarylpropionitrile (DPN). Subsequently, the mRNA or protein expression levels of ESR1/2, peroxisome proliferator activated receptor α (PPARα), CD36 molecule (CD36), fatty acid synthase (FASN), perilipin 2 (PLIN2), phosphorylated acetyl­CoA carboxylase α (p­ACACA), p­AKT serine/threonine kinase (p­AKT) and p­mitogen­activated protein kinase 8 (p­MAPK8) were analyzed in skeletal muscle or in C2C12 cells by reverse transcription­semi­quantitative polymerase chain reaction and western blotting. The present results suggested that treatment with E2 inhibited OVX­induced body weight gain, TG accumulation and insulin resistance. The protein or mRNA expression levels of ESR1, CD36, PPARα, p­ACACA and p­AKT were decreased, whereas the protein or mRNA expression levels of ESR2, PLIN2, FASN and p­MAPK8 were increased in the OVX group. Of note, treatment with E2 restored the expression levels of the aforementioned factors. In C2C12 cells, treatment with E2 or PPT reversed the alterations induced by treatment with PA. In contrast, pretreatment with DPN did not influence the effect of PA. Collectively, E2 was able to interact with ESR1, thus activating the CD36­PPARα pathway, decreasing the level of TG in the muscles and improving insulin resistance in skeletal muscles and C2C12 cells.


Assuntos
Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Triglicerídeos/biossíntese , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Resistência à Insulina , Camundongos , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Ovariectomia , Ácido Palmítico/farmacologia , Perilipina-2/genética , Perilipina-2/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
19.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083300

RESUMO

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp-/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp-/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp-/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp-/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp-/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp-/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp-/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC-Tiparp-/- mice. Our study reveals that Tiparp-/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.


Assuntos
Ascite Quilosa/induzido quimicamente , Ascite Quilosa/enzimologia , Metilcolantreno/toxicidade , Poli(ADP-Ribose) Polimerases/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos Azo/farmacologia , Ascite Quilosa/patologia , Citocinas/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Knockout , Poli(ADP-Ribose) Polimerases/genética , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Análise de Sobrevida
20.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067640

RESUMO

Copper(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized. The copper(II) complexes [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4, [HC(COOH)(pz)2]2Cu(ClO4)2 (pzMe2 = 3,5-dimethylpyrazole; pz = pyrazole) were prepared by the reaction of Cu(ClO4)2·6H2O with bis(3,5-dimethylpyrazol-1-yl)acetic acid (HC(COOH)(pzMe2)2) and bis(pyrazol-1-yl)acetic acid (HC(COOH)(pz)2) ligands in ethanol solution. The copper(II) complex [HC(COOH)(tz)2]2Cu(ClO4)2·CH3OH (tz = 1,2,4-triazole) was prepared by the reaction of Cu(ClO4)2·6H2O with bis(1,2,4-triazol-1-yl)acetic acid (HC(COOH)(tz)2) ligand in methanol solution. The synthesized Cu(II) complexes, as well as the corresponding uncoordinated ligands, were evaluated for their cytotoxic activity in monolayer and 3D spheroid cancer cell cultures with different Pt(II)-sensitivity. The results showed that [HC(COOH)(pzMe2)2]Cu[HC(COO)(pzMe2)2]·ClO4 was active against cancer cell lines derived from solid tumors at low IC50 and this effect was retained in the spheroid model. Structure and ultra-structure changes of treated cancer cells analyzed by Transmission Electron Microscopy (TEM) highlighted the induction of a cytoplasmic vacuolization, thus suggesting paraptotic-like cancer cell death triggering.


Assuntos
Complexos de Coordenação/química , Pirazóis/química , Triazóis/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Cobre/química , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/farmacologia , Esferoides Celulares/efeitos dos fármacos , Triazóis/síntese química , Triazóis/farmacologia
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