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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 -
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 -
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 -
Molecules (Basel, Switzerland) May 2021The synthesis of novel triphenyltin(IV) compounds, PhSnL ( = 1-3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), , and the new propanoic acid derivatives...
The synthesis of novel triphenyltin(IV) compounds, PhSnL ( = 1-3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), , and the new propanoic acid derivatives 3-(4,5-bis(4-methoxylphenyl)oxazol-2-yl)propanoic acid, , and 3-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)propanoic acid, , has been performed. The ligands represent commercial drugs or their derivatives and the tin complexes have been characterized by standard analytical methods. The in vitro antiproliferative activity of both ligands and organotin(IV) compounds has been evaluated on the following tumour cell lines: human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29), breast cancer (MCF-7), and hepatocellular cancer (HepG2), as well as on normal mouse embryonic fibroblast cells (NIH3T3) with the aid of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. Contrary to the inactive ligand precursors, all organotin(IV) carboxylates showed very good activity with IC values ranging from 0.100 to 0.758 µM. According to the CV assay (IC = 0.218 ± 0.025 µM), complex demonstrated the highest cytotoxicity against the caspase 3 deficient MCF-7 cell line. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated a two-fold lower concentration of tin in MCF-7 cells in comparison to platinum. To investigate the mechanism of action of the compound on MCF-7 cells, morphological, autophagy and cell cycle analysis, as well as the activation of caspase and ROS/RNS and NO production, has been performed. Results suggest that induces caspase-independent apoptosis in MCF-7 cells.
Topics: Animals; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Gentian Violet; HT29 Cells; HeLa Cells; Humans; In Vitro Techniques; Inhibitory Concentration 50; Ligands; MCF-7 Cells; Mass Spectrometry; Metals; Mice; NIH 3T3 Cells; Neoplasms; Organotin Compounds; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 34071809
DOI: 10.3390/molecules26113199 -
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 -
Journal of the American Chemical Society Aug 2023The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β, = 5730 years) as well as in positron emission...
The need for carbon-labeled radiotracers is increasingly higher in drug discovery and development (carbon-14, β, = 5730 years) as well as in positron emission tomography (PET) for in vivo molecular imaging applications (carbon-11, β, = 20.4 min). However, the structural diversity of radiotracers is still systematically driven by the narrow available labeled sources and methodologies. In this context, the emergence of carbon dioxide radical anion chemistry might set forth potential unexplored opportunities. Based on a dynamic isotopic equilibration between formate salts and [C, C, C]CO, C-labeled radical anion CO could be accessed under extremely mild conditions within seconds. This methodology was successfully applied to hydrocarboxylation and dicarboxylation reactions in late-stage carbon isotope labeling of pharmaceutically relevant compounds. The relevance of the method in applied radiochemistry was showcased by the whole-body PET biodistribution profile of [C]oxaprozin in mice.
Topics: Mice; Animals; Carbon Isotopes; Carbon Radioisotopes; Carbon Dioxide; Salts; Tissue Distribution; Anions; Positron-Emission Tomography; Formates; Isotope Labeling
PubMed: 37486080
DOI: 10.1021/jacs.3c04679 -
Chemico-biological Interactions Sep 2023Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this...
Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide.
Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this characteristic potently attenuate the catalytic function of CYP4A11, drug-drug interactions may occur. Acidic non-steroidal anti-inflammatory drugs (NSAIDs) possess a carboxylic acid in their structure. However, it remains unclear whether these drugs inhibit CYP4A11 activity. The present study examined the inhibitory effects of acidic NSAIDs on CYP4A11 activity using human liver microsomes (HLMs) and recombinant CYP4A11. Sulindac sulfide, ibuprofen, and flurbiprofen effectively decreased the luciferin-4A O-demethylase activity of HLMs and recombinant CYP4A11 (inhibition rates of 30-96% at an inhibitor concentration of 100 μM), while salicylic acid, aspirin, diclofenac, mefenamic acid, indomethacin, etodolac, ketoprofen, loxoprofen, S-naproxen, pranoprofen, zaltoprofen, and oxaprozin exhibited weaker inhibitory activity (inhibition rates up to 23%). Among the drugs tested, sulindac sulfide was the most potent inhibitor of CYP4A11 activity. A kinetic analysis of the inhibition of CYP4A11 by sulindac sulfide revealed mixed-type inhibition for HLMs (K = 3.38 μM) and recombinant CYP4A11 (K = 4.19 μM). Sulindac sulfide is a pharmacologically active metabolite of sulindac (sulfoxide form), which is also oxidized to sulindac sulfone. To elucidate the role of a sulfur atom of sulindac sulfide in the inhibition of CYP4A11, the inhibitory effects of sulindac sulfide and its oxidized forms on CYP4A11 activity were examined. The potency of inhibition against HLMs was greater in the order of sulindac sulfide, sulindac, and sulindac sulfone; IC values were 6.16, 52.7, and 71.6 μM, respectively. The present results indicate that sulindac sulfide is a potent inhibitor of CYP4A11. These results and the molecular modeling of CYP4A11 with sulindac sulfide and its oxidized forms suggest that a sulfur atom of sulindac sulfide as well as its carboxylic acid play important roles in the inhibition of CYP4A11.
Topics: Humans; Sulindac; Carboxylic Acids; Kinetics; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37499995
DOI: 10.1016/j.cbi.2023.110644 -
Biomedicines Jun 2021SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase...
Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.
PubMed: 34209525
DOI: 10.3390/biomedicines9070749