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1.
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
2.
Biomed Res Int ; 2019: 9165648, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240229

RESUMO

Inflammation is a consequence of an array of biological reactions that occur in response to pain sensation, local injury, and cell damage. A large number of studies have demonstrated that quercetin and other flavonoids show anti-inflammatory effects; thus, in the present work, we evaluated a triazine-phenol derivative (TP derivative) compound as a possible drug candidate with anti-inflammatory activity. This compound was studied as a possible anti-inflammatory drug using synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and mass spectrometry (MS). The derivative of melamine was evaluated for its antioxidant activity and exhibited good DPPH and FRAP antioxidant activity. Additionally, we evaluated the putative effect of the molecule on the COX-2 enzyme through molecular dynamic simulation (MDS), and the result suggested that the TP derivative is a potential anti-inflammatory agent that can interact with the COX-2 enzyme because of the high number of protein-ligand interactions observed with MDS. Finally, the study of theoretical physicochemical properties, the observation of low toxicity (hemolysis assay), and the evaluation of oral bioavailability of the TP derivative showed that it is a possible anti-inflammatory drug candidate.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/análise , Antioxidantes/química , Triazinas/análise , Triazinas/química , Compostos de Bifenilo , Simulação por Computador , Ciclo-Oxigenase 2/química , Eritrócitos , Flavonoides/farmacologia , Hemólise , Técnicas In Vitro , Inflamação , Ligantes , Simulação de Acoplamento Molecular , Fenol/farmacologia , Picratos , Quercetina/farmacologia
3.
Molecules ; 24(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247960

RESUMO

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae, which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antitussígenos/farmacologia , Produtos Biológicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Hidantoínas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antitussígenos/síntese química , Antitussígenos/química , Produtos Biológicos/química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Drogas , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Hidantoínas/síntese química , Hidantoínas/química , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 20(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174295

RESUMO

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein's ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Descoberta de Drogas/métodos , Simulação de Acoplamento Molecular/métodos , Sítios de Ligação , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Ligação Proteica
5.
Phytomedicine ; 62: 152951, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31136898

RESUMO

BACKGROUND: Sphaeranthus africanus has been used in traditional Vietnamese medicine to treat sore throat, and to relieve pain and swelling. However, the anti-inflammatory activity of this plant had not yet been investigated. Previously, we isolated five carvotacetones (1-5) from this plant that displayed cytotoxicity against several cancer cell lines. PURPOSE: The objective of this study was to isolate further constituents from S. africanus and to investigate the anti-inflammatory activity of all constituents. Furthermore, the anti-proliferative activity of the newly isolated compounds was evaluated. STUDY DESIGN AND METHODS: Compounds were isolated from the upper parts of S. africanus by chromatographic methods. Structures were determined using spectroscopic techniques, like NMR and MS. All nine compounds isolated from S. africanus were evaluated for inhibitory activity against COX-1 and COX-2 isoenzymes in-vitro, COX-2 mRNA expression and influence on NO production. The anti-proliferative activities of newly isolated compounds (6-9) were evaluated by XTT viability assay with four cancer cell lines, namely CCRF-CEM, MDA-MB-231, HCT-116, and U-251 cells. RESULTS: Two diastereomeric carvotacetones (3-angeloyloxy-5-[2″S,3″R-dihydroxy-2″-methyl-butanoyloxy]-7-hydroxycarvotacetone (6) and 3-angeloyloxy-5-[2″R,3″R-dihydroxy-2″-methyl-butanoyloxy]-7-hydroxycarvotacetone (7), asperglaucide (8) and chrysoplenol D (9) were isolated from S. africanus. COX-1 and COX-2 assays of compounds 1-9 revealed that compounds 1 and 2 possess potent and selective COX-2 inhibitory activity with IC50 values of 3.6 and 0.5 µM, respectively. COX-2 gene expression assay showed that some carvotacetones exhibited inhibitory effects on COX-2 gene expression in THP-1 macrophages. Compound 4 is the most active compound inhibiting the synthesis of COX-2 by 55% at 2.06 µM. In the iNOS assay, all seven carvotacetones inhibited NO production in BV2 and RAW cell lines with IC50 values ranging from 0.2 to 2.9 µM. Compound 4 showed potent inhibitory activity with IC50 values of 0.2 µM in both BV2 and RAW cell lines. Molecular docking studies revealed the binding orientations of 1 and 2 in the active sites of COX-2. XTT assay of the newly isolated compounds revealed that the two isomeric carvotacetones (6-7) exhibited considerable anti-proliferative activity against four cancer cell lines (CCRF-CEM, MDA-MB-231, HCT-116, U-251) with IC50 values ranging from 1.23 to 8 µM. CONCLUSION: For the first-time, the diastereomeric carvotacetones (6-7) were isolated as separate compounds, and their anti-proliferative activity was determined. Selective COX-2 inhibitory, COX-2 mRNA expression and NO production inhibitory activities by some of the major constituents of S. africanus supports the traditional medical application of this plant for the treatment of inflammation-related disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Inibidores de Ciclo-Oxigenase/farmacologia , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Linhagem Celular , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Macrófagos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Componentes Aéreos da Planta/química , Plantas Medicinais/química
6.
Food Chem ; 289: 204-214, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30955604

RESUMO

The objective was to identify and characterize peptides from digested total protein (DTP) and isolated protein fractions (DPF), and their potential antioxidant, anti-inflammatory and anti-atherosclerotic effects, from chia seed (Salvia hispanica L.). Total protein and protein fractions from chia seed underwent simulated gastrointestinal digestion. The sequence, physicochemical properties, and biological potential of peptides were determined using chemical, in silico, and biochemical assays. Peptides from DTP (n = 9) and DPF albumin (n = 12), globulin (n = 11), prolamin (n = 5) and glutelin (n = 17) had interaction with cyclooxygenase-2 (COX-2), p65- nuclear factor kappa B, lipoxygenase-1 (LOX-1) and toll-like receptor 4 (p < 0.05). DTP, and digested albumin, globulin, and glutelin showed scavenging capacity for superoxide, hydrogen peroxide, nitric oxide and DPPH (1,1-diphenyl-2-picrylhydrazyl), and inhibition of 5-LOX, COX-1-2, and inducible nitric oxide synthase (iNOS) enzymes (p < 0.05). Chia seed proteins has peptides with potential beneficial health effects highlighting the importance of chia consumption.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas de Plantas/química , Salvia/metabolismo , Antioxidantes/química , Araquidonato 5-Lipoxigenase/química , Sítios de Ligação , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Simulação de Acoplamento Molecular , Óxido Nítrico/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Peptídeos/análise , Peptídeos/química , Proteínas de Plantas/metabolismo , Estrutura Terciária de Proteína , Sementes/metabolismo
7.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991684

RESUMO

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.


Assuntos
Anti-Inflamatórios não Esteroides/química , Benzoatos/química , Simulação por Computador , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Propionatos/química , Animais , Humanos , Camundongos , Ratos
8.
J Biol Chem ; 294(22): 8690-8698, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31000626

RESUMO

Many indomethacin amides and esters are cyclooxygenase-2 (COX-2)-selective inhibitors, providing a framework for the design of COX-2-targeted imaging and cancer chemotherapeutic agents. Although previous studies have suggested that the amide or ester moiety of these inhibitors binds in the lobby region, a spacious alcove within the enzyme's membrane-binding domain, structural details have been lacking. Here, we present observations on the crystal complexes of COX-2 with two indomethacin-dansyl conjugates (compounds 1 and 2) at 2.22-Å resolution. Both compounds are COX-2-selective inhibitors with IC50 values of 0.76 and 0.17 µm, respectively. Our results confirmed that the dansyl moiety is localized in and establishes hydrophobic interactions and several hydrogen bonds with the lobby of the membrane-binding domain. We noted that in both crystal structures, the linker tethering indomethacin to the dansyl moiety passes through the constriction at the mouth of the COX-2 active site, resulting in displacement and disorder of Arg-120, located at the opening to the active site. Both compounds exhibited higher inhibitory potency against a COX-2 R120A variant than against the WT enzyme. Inhibition kinetics of compound 2 were similar to those of the indomethacin parent compound against WT COX-2, and the R120A substitution reduced the time dependence of COX inhibition. These results provide a structural basis for the further design and optimization of conjugated COX reagents for imaging of malignant or inflammatory tissues containing high COX-2 levels.


Assuntos
Domínio Catalítico , Membrana Celular/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Compostos de Dansil/química , Indometacina/química , Animais , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Fluorescência , Concentração Inibidora 50 , Cinética , Camundongos , Modelos Moleculares , Fatores de Tempo
9.
Life Sci ; 225: 29-38, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940538

RESUMO

AIMS: Spontaneously hypertensive rats (SHR) exhibit impaired endothelial vasodilation and enhanced vasoconstriction. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Sild) potentiates the nitric oxide (NO)-mediated effects exerting antioxidative and anti-inflammatory actions. In the present study, we hypothesized that Sild could improve endothelial function in SHR. MATERIALS AND METHODS: Male rats were treated daily for 60 days by oral gavage with Sild (45 mg/kg) before the onset of the hypertensive state (pre-hypertensive protocol). The aortic relaxation to acetylcholine (ACh), sodium nitroprusside (SNP) and the phenylephrine (Phe)-induced contraction was evaluated in SHR. Protein expression of eNOS, p-eNOS, caveolin, COX-1, COX-2, ERK and p-ERK was measured by Western blot. KEY FINDINGS: Resting blood pressure was not modified by Sild administration. Treatment with Sild did not alter the relaxation response to SNP but improved the ACh-induced relaxation and reduced Phe-induced contraction in aortic rings from SHR. This protective effect of Sild could be attributed to reduced superoxide anions (O2-) generation, cyclooxygenase type 2 (COX-2) protein downregulation and increased NO bioavailability. SIGNIFICANCE: Sild improves endothelial function in SHR aorta without affecting resting blood pressure values. These results indicate that PDE5 inhibition has a potential role in the improvement of vascular function and could be an adjuvant in the treatment of essential hypertension.


Assuntos
Cardiomegalia/prevenção & controle , Ciclo-Oxigenase 2/química , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Citrato de Sildenafila/administração & dosagem , Vasodilatadores/administração & dosagem , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos SHR
10.
Bioorg Med Chem ; 27(10): 2112-2121, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981607

RESUMO

A series of bi-functional 7-hydroxycoumarin platinum(IV) complexes were synthesized, characterized, and evaluated for antitumor activities. The 7-hydroxycoumarin platinum(IV) complexes display moderate to effective antitumor activities toward the tested cell lines and show much potential in overcoming drug resistance of platinum(II) drugs. In reducing microenvironment, the title compounds could be reduced to platinum(II) complex accompanied with two equivalents of coumarin units. By a unique mechanism, the 7-hydroxycoumarin platinum(IV) complex attacks DNA via the released platinum(II) compound, meanwhile it also inhibits the activities of cyclooxygenase by coumarin fragment. This action mechanism might be of much benefit for reducing tumor-related inflammation in the progress of inhibiting tumor proliferation and overcoming cisplatin resistance. The incorporation of 7-hydroxycoumarin leads to significantly enhanced platinum accumulation in both whole tumor cells and DNA. The HSA interaction investigation reveals that the tested coumarin platinum(IV) compound could effectively combine with HSA via van der Waals force and hydrogen bond.


Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Platina/química , Umbeliferonas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dano ao DNA/efeitos dos fármacos , Humanos , Ligação Proteica , Albumina Sérica/química , Albumina Sérica/metabolismo
11.
Bioorg Med Chem ; 27(9): 1789-1794, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898436

RESUMO

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were -13.80 kcal/mol for COX-1 and -18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Indometacina/química , Sítios de Ligação , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Indometacina/metabolismo , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Eletricidade Estática
12.
Bioorg Chem ; 85: 541-557, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30807897

RESUMO

New thiophene and annulated thiophene pyrazole hybrids were synthesized and screened for their in vitro COX-1/COX-2 enzymatic inhibition and in vivo anti-inflammatory activities. All compounds were more COX-2 selective inhibitors than COX-1 with compound 13 exhibiting the highest COX-2 selectivity index. Compounds 3, 6a, 9 and 11 were the most promising in the acute anti-inflammatory assay while compounds 3, 5, 6a, 6c, 9, 10, 11 and 13 exerted promising anti-inflammatory activity in the sub-acute anti-inflammatory assay. Compounds 3, 6a, 6c, 9, 10 and 11 were evaluated for their ED50 values and were more potent than diclofenac sodium while compounds 6a, 6c and 9 were of greater potency than celecoxib with compound 6a being the most potent showing ED50 = 0.033 mmol/kg. These compounds were non-toxic and proved to be gastrointestinal safe compared to indomethacin, diclofenac sodium and celecoxib. Docking studies into COX-2 active site (PDB code 3LN1) revealed that compounds 3, 6a, 6c, 9, 10, 11 and 13 had binding modes and energies comparable to that of celecoxib. Compounds 3, 9, 10 and 11 complied with Lipinski's RO5 while compounds 6a and 6c showed one violation whereas compound 13 deviated by 2 violations. Compounds 6a, 6c and 13 showed 100% plasma protein binding (PPB) and showed no aqueous solubility while compounds 3, 10 and 11 demonstrated the best drug likeness model scores. Therefore, the thiophene analog 3 and the thienopyrimidine derivatives 10 and 11 are promising anti-inflammatory candidates that exert moderate selective COX-2 inhibition with acceptable physicochemical properties.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tiofenos/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/toxicidade , Sítios de Ligação , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/toxicidade , Desenho de Drogas , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Pirimidinas/síntese química , Pirimidinas/toxicidade , Ratos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/toxicidade
13.
Biochimie ; 160: 28-33, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30763639

RESUMO

Osteoarthritis (OA) is one of the main locomotor disorders in horses. Although nonsteroidal anti-inflammatory drugs are the first-line treatment for OA, opioids could also be used. In previous studies, opioids showed promising anti-inflammatory and analgesic effects. In this study, we aimed to investigate the effects of two opioids (morphine and methadone) against inflammation in lipopolysaccharide (LPS)-stimulated synoviocytes by analyzing microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. Synoviocytes were obtained from the joints at the distal limbs of dead animals. The cytotoxic effects of LPS, morphine, and methadone were investigated by using a cell viability assay with crystal violet dye. Synoviocytes were treated with LPS, LPS plus morphine, or LPS plus methadone for 3, 6, and 12 h, and mPGES-1 and PTGS2 expression was measured using real-time polymerase chain reaction. LPS, and morphine did not affect the viability of synoviocytes, even at high concentrations. LPS treatment increased mPGES-1 and PTGS2 expression, whereas morphine inhibited the increase in mPGES-1 and PTGS2 expression in LPS-stimulated synoviocytes. Methadone did not inhibit mPGES-1 or PTGS2 expression. These results suggest that morphine may exhibit anti-inflammatory effect; therefore, it might be beneficial for the treatment of OA.


Assuntos
Ciclo-Oxigenase 2/química , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Metadona/farmacologia , Microssomos/enzimologia , Morfina/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Sinoviócitos/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Cavalos , Inflamação/induzido quimicamente , Inflamação/enzimologia , Masculino , Sinoviócitos/imunologia , Sinoviócitos/metabolismo , Sinoviócitos/patologia
14.
Interdiscip Sci ; 11(2): 153-169, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29236213

RESUMO

The rate-limiting enzyme cyclooxygenase-2 (COX-2) is considered as an insightful prognostic target for non-small cell lung cancer (NSCLC) therapy. Now, administration and prolonged utilization of selective COX-2 inhibitors (COXIBs) towards moderating the NSCLC has been associated with different side effects. In the present study, we focused on the structure-based drug repositioning approaches for predicting therapeutic potential de novo candidates for human COX-2. Due to discrepancies in the eminence of x-ray diffraction structures, creates a big barrier in drug discovery approach. Hence, the adaptable COX-2 structure was investigated using multi-template modeling method. Next, a dataset of twenty-six celebrex-associated optimized scaffolds were screened from ZINC database. Comparative docking approaches were then utilized to identify five compounds as best binders to the active site of COX-2 structures and strongly agree with enormous experimental consequences. MD simulations of regarded protein-ligand complexes reveals that lead molecules were stabilized dynamically in inside the cyclooxygenase site by forming potential salt bridges with Tyr348, Tyr385 and Ser530 residues. These significant results revealed that, identified druggables could prevent the tyrosyl radicals and prostaglandin production that reduces NSCLC progression. Furthermore, pharmacokinetics assets of respected ligands were analyzed, which incorporates similarity ensemble approach, druglikeness and ADMET properties. Finally, the identified novel candidates could serve as COX-2 inhibitors for NSCLC therapy, and coxibs are the best choices for designing new scaffolds to treat cyclooxygenases regard disorders.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Reposicionamento de Medicamentos , Ciclo-Oxigenase 2/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Ligações de Hidrogênio , Ligantes , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
15.
Mol Carcinog ; 58(1): 31-41, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30182439

RESUMO

Previous studies have demonstrated that the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib shows efficacy against multiple cancers, including hepatocellular carcinoma. However, whether celecoxib is effective in alleviating steatosis during hepatocarcinogenesis is unknown. In a rapid hepatocellular carcinoma (HCC) mouse model established via hydrodynamic transfection of activated forms of AKT and c-Met proto-oncogenes, we investigated the antisteatotic and anticarcinogenic efficacy of celecoxib in vivo. Multiple HCC cell lines were employed for in vitro evaluation. Additionally, immunoblotting, immunohistochemistry, hematoxylin and eosin staining and Oil Red O staining were applied for mechanistic investigation. The results revealed that if celecoxib was administered in the early stage of AKT/c-Met-induced HCC, it resulted in disease stabilization. Moreover, celecoxib could alleviate lipid accumulation in the HCC mice and in an oleic acid-induced in vitro hepatic steatosis model. Further evidence at the molecular level indicated that celecoxib down-regulated the expression of phospho-ERK (Thr202/Tyr204) and proliferating cell nuclear antigen (PCNA) in the HCC mice. In addition, celecoxib efficiently repressed the phosphor-Akt (Thr308)/fatty acid synthase (FASN) axis both in vivo and in vitro. Altogether, this study suggests that celecoxib exerts its antilipogenic efficacy by targeting a COX-2/AKT/FASN cascade, which contributes to its ability to delay hepatocarcinogenesis.


Assuntos
Carcinoma Hepatocelular/prevenção & controle , Celecoxib/farmacologia , Ciclo-Oxigenase 2/química , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Apoptose , Carcinogênese , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células , Inibidores de Ciclo-Oxigenase 2/farmacologia , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Camundongos , Ácido Oleico/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Cell Biochem ; 120(1): 452-460, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30191609

RESUMO

The benefits associated with resveratrol (Resv; 3,4',5-trihydroxy-trans-stilbene) are known for a long time. The therapeutic properties of Resv are observed in diseases like cancer, neurological disorders, atherosclerosis, aging, inflammation, etc. Multiple studies suggest that the beneficial properties of Resv are due to its binding to targets in multiple pathways. The same has been reflected in inflammation, where Resv has been shown to inhibit nuclear factor κ light-chain enhancer of activated B cells in the toll-like receptor 4 (TLR4) pathway. There are multiple cellular targets which bind to Resv, however the mode and the key interactions involved remain elusive for many of them. In the current work, we have investigated the structural insights of Resv with three of its binding partners involved in the inflammatory TLR4 signaling pathway. Through a structure-based modelling and molecular dynamics study, we have unraveled the molecular and atomic interactions involved in the Resv-binary complexes of inhibitor of κB kinase, cyclooxygeanse-2, and tank-binding kinase I, all three of which are key players in TLR4 inflammatory signaling. This study is the latest addition to the investigations of the structural partners of Resv and its molecular interactions.


Assuntos
Ciclo-Oxigenase 2/química , Quinase I-kappa B/química , Extratos Vegetais/química , Proteínas Serina-Treonina Quinases/química , Resveratrol/química , Receptor 4 Toll-Like/metabolismo , Sítios de Ligação , Proteínas de Transporte/química , Cristalização , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Quinase I-kappa B/antagonistas & inibidores , Inflamação/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Projetos de Pesquisa , Sesquiterpenos/química , Vitis/química
17.
J Inorg Biochem ; 190: 38-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352314

RESUMO

Copper complexes are hopeful anticancer drugs due to their multifacet biological properties and high biocompatibility. Inflammatory environment plays an important role in tumor progression and affects the body response to chemotherapeutic agents. A copper(II) complex CuLA with a phenanthroline derivative N-(1,10-phenanthrolin-5-yl)-nonanamide (L) and two aspirin anions (A) as the ligands was synthesized. CuLA effectively induces mitochondrial dysfunction and promotes early-apoptosis in SKOV-3 cells; moreover, it suppresses the expression of cyclooxygenase-2, a key enzyme involved in inflammatory response, in lipopolysaccharide stimulated RAW 264.7 cells. By contrast, the analogue complex CuL without aspirin ligand shows similar influences on cellular redox homeostasis and cell cycle progression but relatively low cytotoxic activity due to its mild effect on mitochondrial function; more importantly, it lacks inhibition to cyclooxygenase-2. The results demonstrate that CuLA inhibits cancer cells through dual pathways involving DNA damage and mitochondrial dysfunction. The introduction of aspirin not only enhances the antitumour efficacy but also reduces the inflammatory threat. Copper complexes with both antitumor and anti-inflammatory activities may represent a new type of multifunctional metal complexes in hope to be developed into novel metallodrugs.


Assuntos
Antineoplásicos/farmacologia , Núcleo Celular/química , Cobre/química , Ciclo-Oxigenase 2/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ciclo-Oxigenase 2/química , Dano ao DNA , Humanos , Mitocôndrias/química
18.
Bioorg Chem ; 82: 86-99, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30278282

RESUMO

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , PPAR gama/agonistas , Pirróis/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Domínio Catalítico , Celecoxib/química , Celecoxib/farmacologia , Celulases/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Drogas , Inibidores de Glicosídeo Hidrolases/efeitos adversos , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/química , Pirróis/efeitos adversos , Pirróis/síntese química , Pirróis/química , Ratos , Ovinos , Úlcera Gástrica/induzido quimicamente , Relação Estrutura-Atividade , Tiazolidinas/efeitos adversos , Tiazolidinas/síntese química , Tiazolidinas/química , alfa-Glucosidases/metabolismo
19.
Curr Comput Aided Drug Des ; 15(4): 277-293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30280671

RESUMO

BACKGROUND: In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme. OBJECTIVE: The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking. METHODS: 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina. RESULTS: Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred_r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred_r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0). CONCLUSION: The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders.


Assuntos
Benzimidazóis/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Drogas , Oxidiazóis/farmacologia , Benzimidazóis/química , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/química , Humanos , Simulação de Acoplamento Molecular , Oxidiazóis/química , Relação Quantitativa Estrutura-Atividade
20.
Chem Biol Drug Des ; 93(3): 290-299, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30294891

RESUMO

The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti-inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8%-57.4% and 0.0%-97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro-inflammatory enzymes, compared to the parent terpenes and non-steroidal anti-inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6-15 within COX-2 and 15-LOX active sites. The relative affinity of the compounds inside the binding sites could be explained by forming non-covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r2  = 0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds.


Assuntos
Anti-Inflamatórios/química , Araquidonato 15-Lipoxigenase/química , Ciclo-Oxigenase 2/química , Medicamentos Sintéticos/química , Terpenos/química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Sítios de Ligação , Domínio Catalítico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica
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