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1.
Bioorg Chem ; 112: 104861, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826984

RESUMO

Microsomal prostaglandin E2 synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC50 mPGES-1 = 0.16 µM; IC50 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.


Assuntos
Androstenóis/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Androstenóis/síntese química , Androstenóis/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Relação Estrutura-Atividade , Adulto Jovem
2.
Bioorg Med Chem Lett ; 41: 127992, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33775835

RESUMO

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE2 levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE2 (IC50: 0.24 µM) in A549 cells via inhibition of mPGES-1 (IC50: 0.49 µM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Sulfonamidas/farmacologia , Células A549 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Fígado/química , Fígado/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
3.
Cell Death Dis ; 12(2): 135, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33542207

RESUMO

Despite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E2 (PGE2), are well-characterized mediators of inflammation. PGE2 is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE2-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE2-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevated Cx3cr1 expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE2 contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.


Assuntos
Quimiocina CX3CL1/metabolismo , Dinoprostona/metabolismo , Inibidores Enzimáticos/farmacologia , Células Epiteliais/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Peritonite/enzimologia , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Adesão Celular , Sobrevivência Celular , Células Cultivadas , Quimiocina CX3CL1/antagonistas & inibidores , Quimiocina CX3CL1/genética , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Feminino , Macrófagos Peritoneais/enzimologia , Macrófagos Peritoneais/imunologia , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Peritonite/genética , Peritonite/imunologia , Fenótipo , Prostaglandina-E Sintases/metabolismo , Regulação para Cima
4.
Sci Rep ; 11(1): 3528, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574423

RESUMO

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70-0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.


Assuntos
Analgésicos/uso terapêutico , Inflamação/tratamento farmacológico , Lapatinib/uso terapêutico , Prostaglandina-E Sintases/genética , Anti-Inflamatórios/uso terapêutico , Mineração de Dados , Reposicionamento de Medicamentos , Humanos , Inflamação/patologia , Neoplasias/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores
5.
Biochim Biophys Acta Gen Subj ; 1865(2): 129800, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33246032

RESUMO

BACKGROUND: Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. METHODS: We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. RESULTS: This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. SIGNIFICANCE: Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.


Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Descoberta de Drogas , Eicosanoides/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Inibidores da Proteína Ativadora de 5-Lipoxigenase/química , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Eicosanoides/metabolismo , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Prostaglandina-E Sintases/metabolismo , Relação Estrutura-Atividade
6.
Sci Rep ; 10(1): 10187, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576928

RESUMO

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is known as an ideal target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs. However, there has been no clinically promising mPGES-1 inhibitor identified through traditional drug discovery and development route. Here we report a new approach, called DREAM-in-CDM (Drug Repurposing Effort Applying Integrated Modeling-in vitro/vivo-Clinical Data Mining), to identify an FDA-approved drug suitable for use as an effective analgesic targeting mPGES-1. The DREAM-in-CDM approach consists of three steps: computational screening of FDA-approved drugs; in vitro and/or in vivo assays; and clinical data mining. By using the DREAM-in-CDM approach, lapatinib has been identified as a promising mPGES-1 inhibitor which may have significant anti-inflammatory effects to relieve various forms of pain and possibly treat various inflammation conditions involved in other inflammation-related diseases such as the lung inflammation caused by the newly identified COVID-19. We anticipate that the DREAM-in-CDM approach will be used to repurpose FDA-approved drugs for various new therapeutic indications associated with new targets.


Assuntos
Anti-Inflamatórios/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Lapatinib/farmacologia , Pneumonia Viral/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Betacoronavirus , COVID-19 , Química Computacional/métodos , Infecções por Coronavirus/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Inflamação/tratamento farmacológico , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/patologia , Prostaglandina-E Sintases/metabolismo , SARS-CoV-2
7.
Br J Pharmacol ; 177(18): 4134-4146, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32449517

RESUMO

BACKGROUND AND PURPOSE: mPGES1 catalyses the production of PGE2 , the most abundant prostanoid related to inflammation and pain in arthritis. mPGES1 is suggested to be a safer and more selective drug target in inflammatory conditions compared to the COX enzymes inhibited by NSAIDs. In the present study, we investigated the effects of the selective mPGES1 inhibitor MF63 on gene expression in primary human chondrocytes from patients with osteoarthritis (OA). EXPERIMENTAL APPROACH: Chondrocytes were isolated from articular cartilage obtained from osteoarthritis patients undergoing knee replacement surgery. The effects of MF63 were studied in the primary chondrocytes with RNA-sequencing based genome-wide expression analysis. The main results were confirmed with qRT-PCR and compared with the effects of the NSAID ibuprofen. Functional analysis was performed with the GO database and interactions between the genes were studied with STRING. KEY RESULTS: MF63 enhanced the expression of multiple metallothionein 1 (MT1) isoforms as well as endogenous antagonists of IL-1 and IL-36. The expression of IL-6, by contrast, was down-regulated. These genes were also essential in functional and interaction network analyses. The effects of MF63 were consistent in qRT-PCR analysis, whereas the effects of ibuprofen overlapped only partly with MF63. There were no evident findings of catabolic effects by MF63. CONCLUSION AND IMPLICATIONS: Metallothionein 1 has been suggested to have anti-inflammatory and protective effects in cartilage. Up-regulation of the antagonists of IL-1 superfamily and down-regulation of the pro-inflammatory cytokine IL-6 also support novel anti-inflammatory and possibly disease-modifying effects of mPGES1 inhibitors in arthritis.


Assuntos
Condrócitos , Prostaglandinas E , Células Cultivadas , Condrócitos/metabolismo , Feminino , Expressão Gênica , Regulação da Expressão Gênica , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Masculino , Microssomos/metabolismo , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo
8.
ChemMedChem ; 15(15): 1398-1407, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32410351

RESUMO

We report an extensive structure-activity relationship optimization of polysubstituted pyrimidines that led to the discovery of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and its difluorinated analogue. These compounds are sub-micromolar inhibitors of PGE2 production (IC50 as low as 12 nM). In order to identify the molecular target of anti-inflammatory pyrimidines, we performed extensive studies including enzymatic assays, homology modeling and docking. The difluorinated analogue simultaneously inhibits two key enzymes of the arachidonic acid cascade, namely mPGES-1 and COX-2, with mPGES-1 inhibition being the principal mechanism of action. Other pyrimidines studied are potent mPGES-1 inhibitors with no observed inhibition of COX-1/2 enzymes. Moreover, the two most potent compounds proved to be significantly effective in vivo in a model of acute inflammation, suppressing carrageenan-induced rat paw edema by 36 and 46 %. The promising results of this study warrant further preclinical evaluation of selected anti-inflammatory candidates.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dinoprostona/antagonistas & inibidores , Edema/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Pirimidinas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Carragenina , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dinoprostona/biossíntese , Relação Dose-Resposta a Droga , Descoberta de Drogas , Edema/induzido quimicamente , Humanos , Camundongos , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
9.
Oncogene ; 39(15): 3179-3194, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32060421

RESUMO

Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.


Assuntos
Dinoprostona/metabolismo , Neoplasias Pulmonares/imunologia , Prostaglandina-E Sintases/metabolismo , Receptores Acoplados a Proteínas G/genética , Evasão Tumoral/genética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , 4-Butirolactona/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Pneumonia/genética , Pneumonia/imunologia , Pneumonia/patologia , Cultura Primária de Células , Prostaglandina-E Sintases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
10.
ChemMedChem ; 15(6): 481-489, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32022480

RESUMO

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile.


Assuntos
Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Tiazolidinedionas/farmacologia , Células A549 , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Prostaglandina-E Sintases/metabolismo , Tiazolidinedionas/síntese química , Tiazolidinedionas/química
11.
Prostaglandins Other Lipid Mediat ; 148: 106409, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31931078

RESUMO

Bladder cancer (BCa) is a common solid tumor marked by high rates of recurrence, especially in non-muscle invasive disease. Prostaglandin E2 (PGE2) is a ubiquitously present lipid mediator responsible for numerous physiological actions. Inhibition of cyclooxygenase (COX) enzymes by the non-steroidal anti-inflammatory (NSAID) class of drugs results in reduced PGE2 levels. NSAID usage has been associated with reductions in cancers such as BCa. Clinical trials using NSAIDs to prevent recurrence have had mixed results, but largely converge on issues with cardiotoxicity. The purpose of this review is to understand the basic science behind how and why inhibitors of PGE2 may be effective against BCa, and to explore alternate therapeutic modalities for addressing the role of PGE2 without the associated cardiotoxicity. We will address the role of PGE2 in a diverse array of cancer-related functions including stemness, immunosuppression, proliferation, cellular signaling and more.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ciclo-Oxigenase 2/química , Dinoprostona/metabolismo , Prostaglandina-E Sintases/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Animais , Ensaios Clínicos como Assunto , Humanos , Neoplasias da Bexiga Urinária/patologia
12.
Prostaglandins Other Lipid Mediat ; 147: 106383, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31698145

RESUMO

Prostaglandin E2 (PGE2) is a lipid mediator of inflammation and cancer progression. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX activity, resulting in decreased PGE2 production and symptomatic relief. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is suggested as a safer therapeutic strategy. This review covers the recent advances in characterization of new mPGES-1 inhibitors in preclinical models and their future clinical applications.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Ensaios Clínicos como Assunto , Humanos , Prostaglandina-E Sintases/metabolismo
13.
Cardiovasc Res ; 116(12): 1972-1980, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31688905

RESUMO

AIMS: Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. METHODS AND RESULTS: Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARß/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. CONCLUSION: These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.


Assuntos
Aorta/enzimologia , Arginina/análogos & derivados , Ciclo-Oxigenase 2/metabolismo , Rim/enzimologia , Prostaglandina-E Sintases/metabolismo , Animais , Aorta/efeitos dos fármacos , Arginina/sangue , Inibidores de Ciclo-Oxigenase 2/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Rim/efeitos dos fármacos , Masculino , Camundongos Knockout , PPAR beta/genética , PPAR beta/metabolismo , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/genética , Prostaglandinas I/sangue , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Epoprostenol/genética , Receptores de Epoprostenol/metabolismo , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo
14.
Biosci Biotechnol Biochem ; 84(4): 757-763, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31868102

RESUMO

Prostaglandin E2 (PGE2), which is a potent pro-inflammatory lipid mediator, is biosynthesized from arachidonic acid by cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Non-steroidal anti-inflammatory drugs (NSAIDs) are used clinically as COX inhibitors, but they have gastrointestinal and cardiovascular side-effects. Thus, the terminal enzyme mPGES-1 holds promise as the next therapeutic target. In this study, we found that the ellagitannins granatin A and granatin B isolated from pomegranate leaves, and geraniin, which is their structural analog, selectively suppressed mPGES-1 expression without affecting COX-2 in non-small cell lung carcinoma A549 cells. The ellagitannins also down-regulated tumor necrosis factor α, inducible nitric oxide synthase, and anti-apoptotic factor B-cell chronic lymphocytic leukemia/lymphoma 2, and induced A549 cells to undergo apoptosis. These findings indicate that the ellagitannins have anti-inflammatory and anti-carcinogenic effects, due to their specific suppression of mPGES-1.Abbreviations: Bcl-2: B-cell chronic lymphocytic leukemia/lymphoma 2; COX: cyclooxygenase; CRE: cAMP response element; DHHDP: dehydrohexahydroxydiphenoyl; Et2O: diethyl ether; EtOAc: ethyl acetate; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; iNOS: inducible nitric oxide synthase; mPGES-1: microsomal prostaglandin E synthase-1; n-BuOH: water-saturated n-butanol; NSAIDs: non-steroidal anti-inflammatory drugs; NF-κB: nuclear factor-κB; PG: prostaglandin; TNF: tumor necrosis factor; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.


Assuntos
Apoptose/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Neoplasias Pulmonares/patologia , Folhas de Planta/química , Romã (Fruta)/química , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Humanos , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , RNA Mensageiro/genética
15.
Sci Transl Med ; 11(516)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666405

RESUMO

Canine studies of spontaneous osteoarthritis (OA) pain add valuable data supporting drug treatment mechanisms that may translate to humans. A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in client-owned dogs with moderate OA pain to evaluate efficacy of LYA, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES1), an EP4 antagonist (LYB), and carprofen, versus placebo. Of 255 dogs screened, 163 were randomized (placebo/LYA/LYB/carprofen: n = 43/39/42/39) and 158 completed treatment. Efficacy versus placebo was assessed using Bayesian mixed-effect model for repeated measure analyses of the Canine Brief Pain Inventory (CBPI) pain interference score (PIS; primary endpoint), pain severity score, and overall impression, as well as the Liverpool Osteoarthritis in Dogs (LOAD) mobility score. The posterior probability that the difference to placebo was <0 at week 2 was 80% for LYA and 54% for LYB for CBPI PIS (both <95% predefined threshold). For secondary endpoints, the posterior probability that the difference to placebo was <0 at week 2 ranged from 89 to 96% for LYA and from 56 to 89% for LYB. The posterior probabilities comparing carprofen to placebo groups were ≥90% for all efficacy endpoints. The proportion of dogs with one or more adverse event was not significantly different from placebo (32.6%) for LYA (35.9%) or carprofen (25.6%), but the rate for LYB (59.5%) was higher versus placebo (P = 0.017). LYA treatment demonstrated consistent improvement in all efficacy measures, suggesting that inhibition of mPGES1 may be an effective treatment for chronic pain associated with OA.


Assuntos
Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Prostaglandina-E Sintases/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Cães , Determinação de Ponto Final , Feminino , Seguimentos , Masculino , Placebos , Probabilidade , Prostaglandina-E Sintases/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Resultado do Tratamento
16.
J Exp Clin Cancer Res ; 38(1): 371, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438982

RESUMO

BACKGROUND: Arachidonic acid (AA) metabolic enzymes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1) and cytochrome P450 (CYP) 4A11 play important roles in glioma angiogenesis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. METHODS: A homology model of human CYP4A11 was constructed using SYBYL-X 2.0. Structure-based virtual screening against COX-2, mPGES-1 and CYP4A11was performed using the Surflex-Dock of the SYBYL suite. The candidates were further evaluated their antiangiogenic activities in a zebrafish embryo and rabbit corneal angiogenesis model. Laser doppler analysis was used to measure tumor perfusion. The expression of CD31 and α-SMA was measured by immunofluorescence. Western blot was used to measure the expression of HIF-1, Akt and p-Akt. The gene expression of FGF-2, G-CSF, PDGF, TGF-ß, Tie-2, VEGF, lncRNA NEAT1 and miR-194-5p were determined using qPCR. The production of FGF-2, TGF-ß and VEGF were analyzed using ELISA. Bioinformatic analysis and luciferase reporter assays confirmed the interaction between lncRNA NEAT1 and miR-194-5p. RESULTS: The nearly 36,043 compounds from the Traditional Chinese Medicine (TCM) database were screened against COX-2, mPGES-1 and CYP4A11 3D models, and the 17 top flavonoids were identified. In zebrafish screening, isoliquiritigenin (ISL) exhibited the most potent antiangiogenic activities with the EC50 values of 5.9 µM. Conversely, the antiangiogenic effects of ISL in the zebrafish and rabbit corneal models were partly reversed by 20-hydroxyeicosatetraenoic acid (20-HETE) or prostaglandin E2 (PGE2). ISL normalized glioma vasculature and improved the efficacy of temozolomide therapy in the rat C6 glioma model. Inhibition of COX-2, mPGES-1 and CYP4A by ISL decreased FGF-2, TGF-ß and VEGF production in the C6 and U87 glioma cells with p-Akt downregulation, which was reversed by Akt overexpression. Furthermore, ISL downregulated lncRNA NEAT1 but upregulated miR-194-5p in the U87 glioma cell. Importantly, lncRNA NEAT1 overexpression reversed ISL-mediated increase in miR-194-5p expression, and thereby attenuated FGF-2, TGF-ß and VEGF production. CONCLUSIONS: Reprogramming COX-2, mPGES-1 and CYP4A mediated-AA metabolism in glioma by flavonoid ISL inhibits the angiogenic Akt- FGF-2/TGF-ß/VEGF signaling through ceRNA effect of miR-194-5p and lncRNA NEAT1, and may serve as a novel therapeutic strategy for human glioma.


Assuntos
Chalconas/farmacologia , Ciclo-Oxigenase 2/química , Citocromo P-450 CYP4A/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neovascularização da Córnea/tratamento farmacológico , Neovascularização da Córnea/metabolismo , Neovascularização da Córnea/patologia , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP4A/metabolismo , Inibidores Enzimáticos/farmacologia , Glioma/irrigação sanguínea , Glioma/metabolismo , Glioma/patologia , Humanos , Masculino , MicroRNAs/genética , Prostaglandina-E Sintases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Coelhos , Ratos , Ratos Wistar , Células Tumorais Cultivadas , Peixe-Zebra
17.
Bioorg Med Chem Lett ; 29(18): 2700-2705, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31362919

RESUMO

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.


Assuntos
Ácidos Carboxílicos/farmacologia , Descoberta de Drogas , Endometriose/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endometriose/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Dor/tratamento farmacológico , Dor/metabolismo , Prostaglandina-E Sintases/metabolismo , Ratos , Relação Estrutura-Atividade
18.
Br J Pharmacol ; 176(24): 4625-4638, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31404942

RESUMO

BACKGROUND AND PURPOSE: Microsomal PGE synthase-1 (mPGES-1), the inducible synthase that catalyses the terminal step in PGE2 biosynthesis, is of high interest as therapeutic target to treat inflammation. Inhibition of mPGES-1 is suggested to be safer than traditional NSAIDs, and recent data demonstrate anti-constrictive effects on vascular tone, indicating new therapeutic opportunities. However, there is a lack of potent mPGES-1 inhibitors lacking interspecies differences for conducting in vivo studies in relevant preclinical disease models. EXPERIMENTAL APPROACH: Potency was determined based on the reduction of PGE2 formation in recombinant enzyme assays, cellular assay, human whole blood assay, and air pouch mouse model. Anti-inflammatory properties were assessed by acute paw swelling in a paw oedema rat model. Effect on vascular tone was determined with human ex vivo wire myography. KEY RESULTS: We report five new mPGES-1 inhibitors (named 934, 117, 118, 322, and 323) that selectively inhibit recombinant human and rat mPGES-1 with IC50 values of 10-29 and 67-250 nM respectively. The compounds inhibited PGE2 production in a cellular assay (IC50 values 0.15-0.82 µM) and in a human whole blood assay (IC50 values 3.3-8.7 µM). Moreover, the compounds blocked PGE2 formation in an air pouch mouse model and reduced acute paw swelling in a paw oedema rat model. Human ex vivo wire myography analysis showed reduced adrenergic vasoconstriction after incubation with the compounds. CONCLUSION AND IMPLICATIONS: These mPGES-1 inhibitors can be used as refined tools in further investigations of the role of mPGES-1 in inflammation and microvascular disease.


Assuntos
Anti-Inflamatórios/farmacologia , Artérias/efeitos dos fármacos , Dinoprostona/biossíntese , Edema/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Tono Muscular/efeitos dos fármacos , Prostaglandina-E Sintases/antagonistas & inibidores , Células A549 , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artérias/enzimologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/imunologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Escherichia coli/genética , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Miografia , Prostaglandina-E Sintases/sangue , Prostaglandina-E Sintases/genética
19.
J Cell Biochem ; 120(11): 19064-19075, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31257629

RESUMO

Co-chaperon p23 has been well established as molecular chaperon for the heat shock protein 90 (Hsp90) that further leads to immorality in cancer cells by providing defense against Hsp90 inhibitors, and as stimulating agent for generating overexpressed antiapoptotic proteins, that is, Hsp70 and Hsp27. The natural compounds such as catechins from Camellia sinensis (green tea) are also well known for inhibition activity against various cancer. However, molecular interaction profile and potential lead bioactive compounds against co-chaperon p23 from green tea are not yet reported. To this context, we study the various secondary metabolites of green tea against co-chaperon p23 using structure-based virtual screening from Traditional Chinese Medicine (TCM) database. Following 26 compounds were obtained from TCM database and further studied for extra precision molecular docking that showed binding score between -10.221 and -2.276 kcal/mol with co-chaperon p23. However, relative docking score to known inhibitors, that is, ailanthone (-4.54 kcal/mol) and gedunin ( 3.60 kcal/mol) along with ADME profile analysis concluded epicatechin (-7.013 kcal/mol) and cis-theaspirone (-4.495 kcal/mol) as potential lead inhibitors from green tea against co-chaperone p23. Furthermore, molecular dynamics simulation and molecular mechanics generalized born surface area calculations validated that epicatechin and cis-theaspirone have significantly occupied the active region of co-chaperone p23 by hydrogen and hydrophobic interactions with various residues including most substantial amino acids, that is, Thr90, Ala94, and Lys95. Hence, these results supported the fact that green tea contained potential compounds with an ability to inhibit the cancer by disrupting the co-chaperon p23 activity.


Assuntos
Antineoplásicos Fitogênicos/química , Camellia sinensis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Prostaglandina-E Sintases , Humanos , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/química
20.
Prostaglandins Other Lipid Mediat ; 144: 106347, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229523

RESUMO

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE2 production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.


Assuntos
Anti-Inflamatórios/farmacologia , Dinoprostona/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Tiazóis/farmacologia , Células A549 , Animais , Anti-Inflamatórios/uso terapêutico , Dinoprostona/biossíntese , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidrazinas/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Tiazóis/uso terapêutico
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