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Chemical Biology & Drug Design May 2019Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory...
Oxaprozin (4,5-diphenyl-2-oxazolepropionic acid) is a non-steroidal, analgesic and antipyretic propionic acid derivative, whose activity in treating inflammatory disorders is well known. The aim of this study was to investigate the ability of oxaprozin to modulate the activity of matrix metalloproteinase 9 (MMP-9), a zinc-dependent endopeptidase involved in a wide range of physiological and pathological events associated with extracellular matrix (ECM) remodelling. The interaction between oxaprozin and MMP-9 was firstly investigated in silico by molecular docking and analysis with LIGPLOT software. Subsequently, the potential inhibitory activity of oxaprozin against MMP-9 and the possible mechanism of the ligand-enzyme interaction were investigated in vitro. Taking into account the in silico findings, MMP-9 can be considered a potential target of oxaprozin, which seems to be able to chelate the catalytic zinc ion through the nitrogen of the oxazole ring and the carboxylate moiety. Moreover, one of the phenyl rings interact with the S1' inhibitor-binding pocket through hydrophobic interaction. Gelatin zymography and enzymatic inhibition assay confirmed the potential role of oxaprozin as a competitive inhibitor of MMP-9. These observations sound particularly interesting if we consider the pathological role of MMP-9, especially evident in inflammatory conditions and cancer. This work may represent a starting point to improve the understanding of the role of oxaprozin, as well as its structural analogues, in modulating the MMP-9 function.
Topics: Binding Sites; Humans; Kinetics; Ligands; Matrix Metalloproteinase 9; Molecular Docking Simulation; Oxaprozin; Protein Structure, Tertiary; Recombinant Proteins; Software
PubMed: 30582279
DOI: 10.1111/cbdd.13468 -
Current HIV Research 2018Two big issues in the study of pathogens are determining how pathogens infect hosts and how the host defends itself against infection. Therefore, investigating...
BACKGROUND
Two big issues in the study of pathogens are determining how pathogens infect hosts and how the host defends itself against infection. Therefore, investigating host-pathogen interactions is important for understanding pathogenicity and host defensive mechanisms and treating infections.
METHODS
In this study, we used omics data, including time-course data from high-throughput sequencing, real-time polymerase chain reaction, and human microRNA (miRNA) and protein-protein interaction to construct an interspecies protein-protein and miRNA interaction (PPMI) network of human CD4+ T cells during HIV-1 infection through system modeling and identification.
RESULTS
By applying a functional annotation tool to the identified PPMI network at each stage of HIV infection, we found that repressions of three miRNAs, miR-140-5p, miR-320a, and miR-941, are involved in the development of autoimmune disorders, tumor proliferation, and the pathogenesis of T cells at the reverse transcription stage. Repressions of miR-331-3p and miR-320a are involved in HIV-1 replication, replicative spread, anti-apoptosis, cell proliferation, and dysregulation of cell cycle control at the integration/replication stage. Repression of miR-341-5p is involved in carcinogenesis at the late stage of HIV-1 infection.
CONCLUSION
By investigating the common core proteins and changes in specific proteins in the PPMI network between the stages of HIV-1 infection, we obtained pathogenic insights into the functional core modules and identified potential drug combinations for treating patients with HIV-1 infection, including thalidomide, oxaprozin, and metformin, at the reverse transcription stage; quercetin, nifedipine, and fenbendazole, at the integration/replication stage; and staurosporine, quercetin, prednisolone, and flufenamic acid, at the late stage.
Topics: Algorithms; Anti-HIV Agents; Computational Biology; Data Mining; Drug Discovery; Gene Expression Profiling; Gene Expression Regulation; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Models, Theoretical; Protein Interaction Mapping; Protein Interaction Maps; Systems Biology
PubMed: 29468972
DOI: 10.2174/1570162X16666180219155324 -
Archiv Der Pharmazie Feb 2018Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In...
Oxaprozin is a popular non-steroidal anti-inflammatory drug (NSAID) and its chronic oral use is clinically restricted due to its gastrointestinal (GI) complications. In order to circumvent the GI complications, oxaprozin was amended as a prodrug in a one-pot reaction using N,N-carbonyldiimidazole as an activating agent. Dextran of average molecular weight (60,000-90,000 Da) was exploited as a carrier in the process of oxaprozin prodrug production by esterification. The structural profiles of the synthesized oxaprozin prodrug were characterized by FT-IR and NMR spectroscopy. The oxaprozin prodrug possessed optimal molecular weight, lipophilicity, partition coefficient, protein binding, and degree of substitution of 52.4%. The release of oxaprozin upon hydrolysis of the prodrug in both simulated gastric fluid and simulated intestinal fluid followed first-order kinetics with 55.2 min of half-life. Varied ADME properties of the prodrug resulted upon Schrodinger's QikProp tool application. Oxaprozin prodrug displayed significant analgesic, antipyretic, and anti-inflammatory activities, with a remarkable decrease in the ulcer index and being devoid of antigenicity in experimental animals. Thus, it is evident that oxaprozin prodrug is a safer oral NSAID without causing any ulcerations.
Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipyretics; Carrageenan; Dose-Response Relationship, Drug; Edema; Female; Hydrolysis; Male; Molecular Structure; Molecular Weight; Oxaprozin; Prodrugs; Propionates; Rats; Rats, Wistar; Structure-Activity Relationship; Ulcer
PubMed: 29283449
DOI: 10.1002/ardp.201700256 -
International Journal of Pharmaceutics Oct 2017Previous studies highlighted an increase of the randomly-methylated-ß-cyclodextrin (RAMEB) solubilizing power towards oxaprozin when used in combination with L-arginine...
Previous studies highlighted an increase of the randomly-methylated-ß-cyclodextrin (RAMEB) solubilizing power towards oxaprozin when used in combination with L-arginine (ARG) or sepiolite nanoclay (SV). Therefore, the aim of this work was to investigate the possibility of maximising the RAMEB solubilizing efficacy by a joined approach based on the entrapment in SV of the drug-RAMEB-ARG complex. The quaternary nanocomposite was prepared by different techniques and characterized for solid state and dissolution properties, compared to ternary drug combinations with RAMEB-ARG, RAMEB-SV or ARG-SV. The dissolution rank order was drug-RAMEB-ARG-SV>>drug-RAMEB-ARG≈drug-RAMEB-SV>>drug-ARG-SV. The new hybrid nanocomposite enabled an increase from 60 up to 90% of oxaprozin dissolution parameters compared to the ternary systems with RAMEB-ARG and RAMEB-SV. Moreover, the lowest solubilizing efficacy of ternary systems with ARG-SV evidenced the specific synergic effect of both ARG and SV with RAMEB in enhancing oxaprozin dissolution properties. The superior performance of the quaternary nanocomposite was maintained after incorporation in a tablet formulation. In vivo studies on rats proved that the developed fast-dissolving tablet formulation, containing oxaprozin as cofused system with RAMEB, ARG and SV was more effective than the marketed tablet in terms of faster and more intense pain relieving effect in the treatment of adjuvant-induced arthritis.
Topics: Aluminum Silicates; Animals; Clay; Drug Carriers; Nanoparticles; Oxaprozin; Propionates; Rats; Solubility; Tablets; beta-Cyclodextrins
PubMed: 28522425
DOI: 10.1016/j.ijpharm.2017.05.033 -
International Journal of Pharmaceutics Dec 2016The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was... (Comparative Study)
Comparative Study
The combined strategy of drug-cyclodextrin (CD) complexation and complex loading into nanocarriers (deformable liposomes or nanostructured lipid carriers (NLC)), was exploited to develop effective topical formulations for oxaprozin transdermal administration. Oxaprozin was loaded as ternary complex with randomly-methylated-ßCD and arginine, selected as the best system in improving drug solubility. The colloidal dispersions, characterized for particle size, zeta-potential and entrapment efficiency, were investigated for drug permeation properties in comparison with a plain drug aqueous suspension, a ternary complex aqueous solution and a plain drug liposomal or NLC dispersion. Experiments with artificial membranes showed that the joined use of CD and both liposomes or NLC enabled a marked increase of the drug permeability (16 and 8 times, respectively) and was significantly more effective (P<0.05) than the drug as ternary complex (3.2 times increase), and the corresponding liposomal or NLC dispersion of plain drug (5.6 and 4.3 times increase, respectively). Experiments with excised human skin confirmed the significantly (P<0.05) better performance of deformable liposomes than NLC in promoting drug permeation; moreover, they evidenced a more marked permeability increase compared to the plain drug (24 and 12 fold, respectively), attributed to a possible enhancer effect of the nanocarriers components and/or of the randomly-methylated-ßCD.
Topics: Administration, Cutaneous; Chemistry, Pharmaceutical; Cyclodextrins; Drug Carriers; Humans; Lipids; Liposomes; Nanoparticles; Nanostructures; Oxaprozin; Particle Size; Permeability; Propionates; Skin; Skin Absorption; Solubility; beta-Cyclodextrins
PubMed: 27825863
DOI: 10.1016/j.ijpharm.2016.11.013 -
The Journal of Organic Chemistry Nov 20162-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The...
2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding α-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%. The anti-inflammatory Oxaprozin was prepared using the α-sulfonyl carbanion strategy along with optimized desulfonylation.
Topics: Alkylation; Magnesium Chloride; Mercuric Chloride; Oxazoles; Oxidation-Reduction; Spectrum Analysis
PubMed: 27441569
DOI: 10.1021/acs.joc.6b01280 -
Journal of Pharmaceutical and... Sep 2016The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-β-cyclodextrin (RameβCD) towards oxaprozin, a very poorly soluble...
The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-β-cyclodextrin (RameβCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RameβCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH≈6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug-CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RameβCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability.
Topics: Amino Acids; Anti-Inflammatory Agents; Arginine; Calorimetry, Differential Scanning; Chemical Phenomena; Oxaprozin; Pharmaceutical Solutions; Powders; Propionates; Solubility; X-Ray Diffraction; X-Rays; beta-Cyclodextrins
PubMed: 27454086
DOI: 10.1016/j.jpba.2016.07.024 -
International Journal of Pharmaceutics Jul 2016A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the...
A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the benefits of these carriers and potentiate their ability to improve the dissolution properties of oxaprozin (OXA), a poorly water-soluble anti-inflammatory drug. Based on previous studies, randomly methylated ß-cyclodextrin (RAMEB) was chosen as the most effective cyclodextrin for OXA complexation. Adsorption equilibrium studies performed on three different clays (sepiolite, attapulgite, bentonite) allowed selection of sepiolite (SV) for its greater adsorption power towards OXA. DSC and XRPD studies indicated drug amorphization in both binary OXA-RAMEB coground and OXA-SV cofused products, due to its complexation or very fine dispersion in the clay structure, respectively. The drug amorphous state was maintained also in the ternary OXA-RAMEB-SV cofused system. Dissolution studies evidenced a clear synergistic effect of RAMEB complexation and clay nanoencapsulation in improving the OXA dissolution properties, with an almost 100% increase in percent dissolved and dissolution efficiency compared to the OXA-RAMEB coground system. Therefore, the proposed combined approach represents an interesting tool for improving the therapeutic effectiveness of poorly soluble drugs, and reducing the CD amount necessary for obtaining the desired drug solubility and dissolution rate increase.
Topics: Aluminum Silicates; Anti-Inflammatory Agents; Bentonite; Clay; Cyclodextrins; Magnesium Compounds; Magnesium Silicates; Nanoparticles; Oxaprozin; Propionates; Silicon Compounds; Solubility; beta-Cyclodextrins
PubMed: 27188644
DOI: 10.1016/j.ijpharm.2016.05.028 -
Tetrahedron Letters Feb 20162-(Halomethyl)-4,5-diphenyloxazoles are effective, reactive scaffolds which can be utilized for synthetic elaboration at the 2-position. Through substitution reactions,...
2-(Halomethyl)-4,5-diphenyloxazoles are effective, reactive scaffolds which can be utilized for synthetic elaboration at the 2-position. Through substitution reactions, the chloromethyl analogue is used to prepare a number of 2-alkylamino-, 2-alkylthio- and 2-alkoxy-(methyl) oxazoles. The 2-bromomethyl analogue offers a more reactive alternative to the chloromethyl compounds and is useful in the C-alkylation of a stabilized (malonate) carbanion as exemplified by a concise synthesis of Oxaprozin.
PubMed: 26989270
DOI: 10.1016/j.tetlet.2016.01.016