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ACS Nano Sep 2023Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with...
Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with these efforts due to the enormous cost, several years of development, and off-target effects like cardiotoxicity. Multicellular organisms such as the () can bridge the gap between and vertebrate testing as they can provide extensive information on systemic toxicity and specific harmful effects through facile experimentation following 3R EU directives on animal use. Since the nematodes' pharynx shares similarities with the human heart, we assessed the general and pharyngeal effects of drugs and polypyrrole nanoparticles (Ppy NPs) using . The evaluation of FDA-approved drugs, such as Propranolol and Racepinephrine reproduced the arrhythmic behavior reported in humans and supported the use of this small animal model. Consequently, Ppy NPs were evaluated due to their research interest in cardiac arrhythmia treatments. The NPs' biocompatibility was confirmed by assessing survival, growth and development, reproduction, and transgenerational toxicity in . Interestingly, the NPs increased the pharyngeal pumping rate of in two slow-pumping mutant strains, JD21 and DA464. Moreover, the NPs increased the pumping rate over time, which sustained up to a day post-excretion. By measuring pharyngeal calcium levels, we found that the impact of Ppy NPs on the pumping rate could be mediated through calcium signaling. Thus, evaluating arrhythmic effects in offers a simple system to test drugs and nanoparticles, as elucidated through Ppy NPs.
Topics: Animals; Humans; Caenorhabditis elegans; Polymers; Pyrroles; Nanoparticles
PubMed: 37624669
DOI: 10.1021/acsnano.3c05245 -
Molecules (Basel, Switzerland) Apr 20221-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed...
1-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed to synthesize new 3,4-dimethyl--pyrrole-2,5-dione derivatives - in the reaction of -substituted amidrazones with 2,3-dimethylmaleic anhydride and evaluate their structural and biological properties. Compounds - were studied by the H-C NMR two-dimensional techniques (HMQC, HMBC) and single-crystal X-ray diffraction (derivatives and ). The anti-inflammatory activity of compounds - was examined by both an anti-proliferative study and a production study on the inhibition of pro-inflammatory cytokines (IL-6 and TNF-α) in anti-CD3 antibody- or lipopolysaccharide-stimulated human peripheral blood mononuclear cell (PBMC) cultures. The antibacterial activity of compounds against , , , , , , and strains was determined using the broth microdilution method. Structural studies of - revealed the presence of distinct and stereoisomers in the solid state and the solution. All compounds significantly inhibited the proliferation of PBMCs in anti-CD3-stimulated cultures. The strongest effect was observed for derivatives -. The strongest inhibition of pro-inflammatory cytokine production was observed for the most promising anti-inflammatory compound .
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Humans; Leukocytes, Mononuclear; Microbial Sensitivity Tests; Pyrroles; Staphylococcus aureus
PubMed: 35566243
DOI: 10.3390/molecules27092891 -
Journal of Enzyme Inhibition and... Dec 2022In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of...
In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found possessed high potency (IC = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN- and IP-10 were induced by in a concentration dependent manner. Finally, we discovered that causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.
Topics: Animals; Mice; Phosphoric Diester Hydrolases; Pyrimidines; Pyrophosphatases; Pyrroles; Structure-Activity Relationship
PubMed: 36069240
DOI: 10.1080/14756366.2022.2119566 -
Cell Death & Disease Apr 2022Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have...
Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT's aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.MCL-1.BIM axis, forcing stressed cells to undergo apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.
Topics: Animals; Humans; Indoles; Mechanistic Target of Rapamycin Complex 1; Mice; Pyrroles; Rhabdoid Tumor; TOR Serine-Threonine Kinases
PubMed: 35484114
DOI: 10.1038/s41419-022-04868-9 -
Molecules (Basel, Switzerland) Nov 2021The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in...
The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, 3-amino-1,5-dihydro-2-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, which were prepared their reaction with carbodiimides.
Topics: Amination; Amines; Carbodiimides; Drug Discovery; Molecular Structure; Pyrroles
PubMed: 34885757
DOI: 10.3390/molecules26237179 -
Aging Jun 2021To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the...
To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 () and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. , MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.
Topics: Binding Sites; CDC2 Protein Kinase; Cell Movement; Cell Proliferation; Cell Survival; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Ligands; Molecular Docking Simulation; Osteosarcoma; Protein Interaction Maps; Protein Kinase Inhibitors; Pyrazoles; Pyrroles; Signal Transduction; Survival Analysis
PubMed: 34156352
DOI: 10.18632/aging.203165 -
Molecules (Basel, Switzerland) May 2020Faced with the ban of some organic UV filters such as octinoxate or avobenzone, especially in Hawaii, it became essential to offer new alternatives that are both...
Faced with the ban of some organic UV filters such as octinoxate or avobenzone, especially in Hawaii, it became essential to offer new alternatives that are both renewable and safe for humans and the environment. In this context, a class of bio-based molecules displaying interesting UV filter properties and great (photo)stability has been developed from Meldrum's acid and bio-based and synthetic -hydroxycinnamic acids, furans and pyrroles. Moreover, -hydroxycinnamic acid-based Meldrum's derivatives possess valuable secondary activities sought by the cosmetic industry such as antioxidant and anti-tyrosinase properties. The evaluation of the properties of mixture of judiciously chosen Meldrum's acid derivatives highlighted the possibility to modulate secondary activity while maintaining excellent UV protection. Meldrum's acid derivatives are not only competitive when benchmarked against organic filters currently on the market (i.e., avobenzone), but they also do not exhibit any endocrine disruption activity.
Topics: Biocompatible Materials; Biphenyl Compounds; Cell Line; Coumaric Acids; Dioxanes; Endocrine Disruptors; Free Radical Scavengers; Furans; Humans; Monophenol Monooxygenase; Picrates; Pyrroles; Ultraviolet Rays
PubMed: 32384797
DOI: 10.3390/molecules25092178 -
Clinical Pharmacology in Drug... Feb 2022Herein, we report a food-effect study of vonoprazan, an oral potassium-competitive acid blocker. In a phase 1, randomized, open-label, crossover study, healthy subjects... (Randomized Controlled Trial)
Randomized Controlled Trial
Herein, we report a food-effect study of vonoprazan, an oral potassium-competitive acid blocker. In a phase 1, randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.
Topics: Administration, Oral; Cross-Over Studies; Food-Drug Interactions; Humans; Potassium; Pyrroles; Sulfonamides
PubMed: 34431240
DOI: 10.1002/cpdd.1009 -
Molecules (Basel, Switzerland) Jul 2023Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly...
Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that -acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-]pyridazinone. Novel compounds --- were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title -acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.
Topics: Hydrazones; Cyclooxygenase Inhibitors; Lipoxygenase Inhibitors; Pyridazines; Pyrroles; Humans; Fibroblasts; Computer Simulation; Cell Membrane Permeability; Cell Line
PubMed: 37513351
DOI: 10.3390/molecules28145479 -
Molecules (Basel, Switzerland) May 2022In this article, we present fluorescent guanidiniocarbonyl-indoles as versatile oxo-anion binders. Herein, the guanidiniocarbonyl-indole (GCI) and...
In this article, we present fluorescent guanidiniocarbonyl-indoles as versatile oxo-anion binders. Herein, the guanidiniocarbonyl-indole (GCI) and methoxy-guanidiniocarbonyl-indole (MGCI) were investigated as ethylamides and compared with the well-known guanidiniocarbonyl-pyrrole (GCP) concerning their photophysical properties as well as their binding behavior towards oxo-anions. Hence, a variety of anionic species, such as carboxylates, phosphonates and sulfonates, have been studied regarding their binding properties with GCP, GCI and MGCI using UV-Vis titrations, in combination with the determination of the complex stoichiometry using the Job method. The emission properties were studied in relation to the pH value using fluorescence spectroscopy as well as the determination of the photoluminescence quantum yields (PLQY). Density functional theory (DFT) calculations were undertaken to obtain a better understanding of the ground-lying electronic properties of the investigated oxo-anion binders. Additionally, X-ray diffraction of GCP and GCI was conducted. We found that GCI and MGCI efficiently bind carboxylates, phosphonates and sulfonates in buffered aqueous solution and in a similar range as GCP (K ≈ 1000-18,000 M, in bis-tris buffer, pH = 6); thus, they could be regarded as promising emissive oxo-anion binders. They also exhibit a visible fluorescence with a sufficient PLQY. Additionally, the excitation and emission wavelength of MGCI was successfully shifted closer to the visible region of the electromagnetic spectrum by introducing a methoxy-group into the core structure, which makes them interesting for biological applications.
Topics: Anions; Arginine; Carboxylic Acids; Fluorescent Dyes; Indoles; Organophosphonates; Pyrroles
PubMed: 35566361
DOI: 10.3390/molecules27093005