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International Journal of Molecular... Sep 2020The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix... (Review)
Review
The crucial role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase-a prostate-specific antigen-in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Chelating Agents; Disease Progression; Drug Design; Drug Screening Assays, Antitumor; Extracellular Fluid; Extracellular Vesicles; Humans; Hydroxamic Acids; Iron; Iron Chelating Agents; Kallikreins; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasm Proteins; Oxaprozin; Peptide Hydrolases; Phenylalanine; Protease Inhibitors; Protein Kinases; Pyridines; Thiophenes; Thiosemicarbazones; Zinc
PubMed: 32948029
DOI: 10.3390/ijms21186805 -
ChemMedChem Dec 2020The radiosynthesis, as well as the in vivo and ex vivo biodistribution of the C radiolabelled 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime (6, [ C]SZV 1287) are...
The radiosynthesis, as well as the in vivo and ex vivo biodistribution of the C radiolabelled 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime (6, [ C]SZV 1287) are reported. SZV 1287 is a novel semicarbazide-sensitive amine oxidase (SSAO) inhibitor and a promising candidate to be a novel analgesic for the treatment of neuropathic pain. Its radiolabelling was developed via a four-step radiosynthesis which started from the reaction of a Grignard reagent with [ C]CO to produce [ C]oxaprozin (3). In the next step this carboxylic acid 3 was directly reduced to yield the corresponding aldehyde, which was then converted into the oxime. [ C]SZV 1287 was administered to male NMRI mice. The animals were examined with dynamic PET/MR imaging for 90 minutes. Biodistribution studies were performed at 10, 30, 60 and 120 minutes post injection. The accumulation of the labelled compound was observed in the brain of the animals. The main excretion pathway was found to be through the liver and intestines. These studies provide preliminary information for pharmacokinetic characterization of the SZV 1287.
Topics: Animals; Carbon Radioisotopes; Male; Mice; Oxazoles; Oximes; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 32935925
DOI: 10.1002/cmdc.202000389 -
Clinical and Experimental Nephrology Mar 2020Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical... (Clinical Trial)
Clinical Trial
BACKGROUND
Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1. The results of nonclinical studies indicated the possibility that the concomitant use of the non-steroidal anti-inflammatory drug oxaprozin affects the pharmacokinetics of dotinurad. We evaluated drug-drug interactions with respect to the pharmacokinetics and safety of dotinurad when co-administered with oxaprozin.
METHODS
This was an open-label, two-period, add-on study in healthy adult males. For a single dose of 4 mg of dotinurad with and without oxaprozin, we compared its pharmacokinetic parameters and evaluated safety.
RESULTS
This study enrolled 12 subjects, 11 of whom completed the study. The geometric mean ratio (90% confidence interval [CI]) of the urinary excretion rate of glucuronate conjugates of dotinurad after co-administration with oxaprozin compared to administration of dotinurad alone was 0.657 (0.624-0.692), while the geometric mean ratios (90% CIs) of the maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity (AUC) were 0.982 (0.945-1.021) and 1.165 (1.114-1.219), respectively. During the study, two adverse events occurred after administration of dotinurad alone and one occurred after administration of oxaprozin alone.
CONCLUSIONS
In comparison with administration of dotinurad alone, co-administration with oxaprozin was associated with a 34.3% decrease in the urinary excretion rate of the glucuronate conjugates of dotinurad, and a 16.5% increase in AUC of dotinurad. However, no clinically meaningful drug-drug interactions were observed. Administration of dotinurad alone was similar safety to co-administration with oxaprozin.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03350386.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Benzothiazoles; Drug Interactions; Glucuronides; Humans; Japan; Male; Oxaprozin; Sulfates; Uricosuric Agents
PubMed: 32076889
DOI: 10.1007/s10157-020-01855-2 -
Journal of Inorganic Biochemistry Feb 2020Upon the interaction of MnCl with the non-steroidal anti-inflammatory drugs oxaprozin or flufenamic acid in the presence of the nitrogen-donors 2,2'-bipyridine or...
Upon the interaction of MnCl with the non-steroidal anti-inflammatory drugs oxaprozin or flufenamic acid in the presence of the nitrogen-donors 2,2'-bipyridine or 1,10-phenanthroline as co-ligands, one dinuclear and two trinuclear Mn(II) complexes were isolated. The complexes were characterized by diverse techniques. The complexes were evaluated for their scavenging activity against free radicals such as hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid). The in vitro binding affinity of the complexes to calf-thymus (CT) DNA and serum albumins was also monitored. In total, we may suggest that the complexes present promising scavenging activity against the radicals tested, and they may bind to CT DNA via intercalation and reversibly to serum albumins.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Coordination Complexes; DNA; Flufenamic Acid; Manganese; Organometallic Compounds; Oxaprozin; Protein Binding; Serum Albumin, Bovine
PubMed: 31707332
DOI: 10.1016/j.jinorgbio.2019.110906 -
Bioorganic & Medicinal Chemistry Oct 2019The human complement fragment 5a (C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and...
The human complement fragment 5a (C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of C5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, C5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of C5a. However, the idea of small molecules, directly neutralizing the function of excessive C5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of C5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against C5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant C5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of C5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on C5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the C5a-C5aR signaling axes.
Topics: Binding Sites; Calorimetry; Cheminformatics; Circular Dichroism; Complement C5a; Drug Repositioning; Fluorescence; Humans; Ligands; Molecular Dynamics Simulation; Proof of Concept Study; Protein Binding; Small Molecule Libraries; Spectrometry, Fluorescence
PubMed: 31447248
DOI: 10.1016/j.bmc.2019.115052 -
Drug Delivery and Translational Research Feb 2020The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman...
The potential for physicochemical driving forces facilitating topical transport of the lipid-soluble drug oxaprozin (OXA) was investigated using surface-enhanced Raman spectroscopy (SERS) in this study. Azone, iontophoresis (IP), and sonophoresis (SP) were combined and performed on mouse skin for the OXA transdermal penetration, and the synergistic effect was analyzed using Raman spectroscopy. The data of characteristic peak intensity were processed with overlapping peak resolving and standard normalization. The results showed that Azone promoted the transdermal penetration of OXA (5.9-fold greater than the OXA concentration of normal penetration); SP enhanced OXA transdermal penetration (5.5-fold); IP enhanced OXA transdermal penetration (4.2-fold); the combined application of Azone and SP (Azone+SP) and SP+IP can improve the enhancement coefficient of OXA transdermal penetration (8.4-fold and 6.1-fold, > 5.9, > 5.5, > 4.2), and their combined application has a synergistic effect; Azone+IP does not have a synergistic effect while the enhancement coefficient of Azone+IP (5.3-fold, < 5.9) and Azone+SP+IP (7.2-fold, < 8.4) was slightly reduced. As for the drug OXA, Azone+SP is an effective method of transdermal penetration.
Topics: Administration, Cutaneous; Animals; Azepines; Iontophoresis; Male; Mice; Oxaprozin; Permeability; Skin Absorption; Spectrum Analysis, Raman; Ultrasonography
PubMed: 31407271
DOI: 10.1007/s13346-019-00664-9 -
Bioorganic Chemistry Aug 2019Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among... (Review)
Review
Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008-2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores.
Topics: Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Development; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 31132600
DOI: 10.1016/j.bioorg.2019.103007