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Cell Death & Disease Feb 2019The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and... (Review)
Review
The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.
Topics: Animals; Calcium Signaling; Diterpenes, Kaurane; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Inflammasomes; Lysosomes; Metals, Alkali; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Nitriles; Protein Processing, Post-Translational; Reactive Oxygen Species; Sulfonamides; Sulfones; Thiazolidines; Thiones; ortho-Aminobenzoates
PubMed: 30755589
DOI: 10.1038/s41419-019-1413-8 -
The Journal of Experimental Medicine Nov 2017The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome...
The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.
Topics: Adult; Animals; Cell Line, Tumor; Cryopyrin-Associated Periodic Syndromes; Diabetes Mellitus, Type 2; Disease Models, Animal; HEK293 Cells; Humans; Immunoblotting; Inflammasomes; Inflammation; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Small Molecule Libraries; Thiazolidines; Thiones
PubMed: 29021150
DOI: 10.1084/jem.20171419 -
Journal of Extracellular Vesicles Mar 2021Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC)...
Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC-induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC-derived extracellular vesicles (EVs) containing prolyl 4-hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin-dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl-2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC-induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC-induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC.
Topics: Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Drug Delivery Systems; Esophageal Squamous Cell Carcinoma; Extracellular Vesicles; Humans; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscular Atrophy; Phosphoglycerate Dehydrogenase; Procollagen-Proline Dioxygenase; Protein Disulfide-Isomerases; Thiazolidines; Thiones
PubMed: 33732415
DOI: 10.1002/jev2.12060 -
Molecules (Basel, Switzerland) Dec 2022HS is an endogenous gas signaling molecule and its multiple biological effects have been demonstrated. The abnormal level of HS is closely related to the occurrence and... (Review)
Review
HS is an endogenous gas signaling molecule and its multiple biological effects have been demonstrated. The abnormal level of HS is closely related to the occurrence and development of many diseases, and HS donors has important pharmacological implications. In recent years, HS donors represented by ADTOH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) are often used to synthesize new 'conjugate' compounds that can release HS and parent drugs. These hybrids retain the pharmacological activity of the parent drugs and HS and have a synergistic effect. ADTOH and parent drug hybrids have become one of the important strategies for the development of HS donor conjugate drugs. This review summarizes molecular hybrids between ADTOH and clinical drugs to provide new ideas for the study of HS donor drug design.
Topics: Hydrogen Sulfide; Signal Transduction; Thiones; Drug Design
PubMed: 36615525
DOI: 10.3390/molecules28010331 -
International Journal of Molecular... Mar 2022Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological... (Review)
Review
Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn, and D609 might act as a potential chelator of Zn, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.
Topics: Bridged-Ring Compounds; Norbornanes; Thiocarbamates; Thiones; Type C Phospholipases
PubMed: 35328726
DOI: 10.3390/ijms23063305 -
Molecules (Basel, Switzerland) Sep 2022Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the... (Review)
Review
Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole-pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.
Topics: Benzimidazoles; Ligands; Pyridines; Pyrroles; Thiones
PubMed: 36234805
DOI: 10.3390/molecules27196268 -
International Journal of Molecular... Feb 2021Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics...
Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog () were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1)-thione () with promising antiproliferative activity (IC equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely , and showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Dihydropyridines; Drug Design; Humans; Melanoma; Mitosis; Molecular Structure; Structure-Activity Relationship; Thiones; Tubulin Modulators; Tumor Cells, Cultured
PubMed: 33671106
DOI: 10.3390/ijms22052462 -
Journal of Industrial Microbiology &... Mar 2019Recent advances and emerging technologies for metabolic pathway engineering and synthetic biology have transformed the field of natural product discovery, production,... (Review)
Review
Recent advances and emerging technologies for metabolic pathway engineering and synthetic biology have transformed the field of natural product discovery, production, and engineering. Despite these advancements, there remain many challenges in understanding how biosynthetic gene clusters are silenced or activated, including changes in the transcription of key biosynthetic and regulatory genes. This knowledge gap is highlighted by the success and failed attempts of manipulating regulatory genes within biosynthetic gene clusters in both native producers and heterologous hosts. These complexities make the choice of native producers versus heterologous hosts, fermentation medium, and supply of precursors crucial factors in achieving the production of the target natural products and engineering designer analogs. Nature continues to serve as inspiration for filling the knowledge gaps and developing new research strategies. By exploiting the evolutionary power of nature, alternative producers, with the desired genetic amenability and higher titers of the target natural products, and new strains, harboring gene clusters that encode evolutionary optimized congeners of the targeted natural product scaffolds, can be discovered. These newly identified strains can serve as an outstanding biotechnology platform for the engineered production of sufficient quantities of the target natural products and their analogs, enabling biosynthetic studies and potential therapeutic applications. These challenges and opportunities are showcased herein using fredericamycin, iso-migrastatin, platencin and platensimycin, the enediynes of C-1027, tiancimycin, and yangpumicin, and the leinamycin family of natural products.
Topics: Adamantane; Aminobenzoates; Aminoglycosides; Aminophenols; Anilides; Bacterial Proteins; Biological Products; Biosynthetic Pathways; Drug Discovery; Enediynes; Gene Expression Regulation, Bacterial; Genes, Bacterial; Lactams; Macrolides; Metabolic Engineering; Multigene Family; Piperidones; Polycyclic Compounds; Protein Conformation; Sequence Analysis, DNA; Streptomyces; Thiazoles; Thiones
PubMed: 30426283
DOI: 10.1007/s10295-018-2094-5 -
Natural Product Reports Mar 2020Covering: 1990 to 2019 Many medicinally-relevant compounds are derived from non-ribosomal peptide synthetase (NRPS) products. Type I NRPSs are organized into large... (Review)
Review
Covering: 1990 to 2019 Many medicinally-relevant compounds are derived from non-ribosomal peptide synthetase (NRPS) products. Type I NRPSs are organized into large modular complexes, while type II NRPS systems contain standalone or minimal domains that often encompass specialized tailoring enzymes that produce bioactive metabolites. Protein-protein interactions and communication between the type II biosynthetic machinery and various downstream pathways are critical for efficient metabolite production. Importantly, the architecture of type II NRPS proteins makes them ideal targets for combinatorial biosynthesis and metabolic engineering. Future investigations exploring the molecular basis or protein-protein recognition in type II NRPS pathways will guide these engineering efforts. In this review, we consolidate the broad range of NRPS systems containing type II proteins and focus on structural investigations, enzymatic mechanisms, and protein-protein interactions important to unraveling pathways that produce unique metabolites, including dehydrogenated prolines, substituted benzoic acids, substituted amino acids, and cyclopropanes.
Topics: Amino Acids; Benzoic Acid; Cyclopropanes; Hydroxylation; Lactams; Macrolides; Netropsin; Peptide Synthases; Proline; Protein Interaction Maps; Pyrroles; Thiazoles; Thiones
PubMed: 31593192
DOI: 10.1039/c9np00047j -
Molecules (Basel, Switzerland) Aug 2022The 1,3-oxazolidine-2-thiones (OZTs) are important chiral molecules, especially in asymmetric synthesis. These compounds serve as important active units in biologically...
The 1,3-oxazolidine-2-thiones (OZTs) are important chiral molecules, especially in asymmetric synthesis. These compounds serve as important active units in biologically active compounds. Herein, carbohydrate anchored OZTs were explored to develop a copper-catalyzed C-S bond formation with aryl iodides. Chemoselective -arylation was observed, with copper iodide and dimethylethylenediamine (DMEDA) as the best ligand in dioxane at 60-90 °C. The corresponding chiral oxazolines were obtained in reasonable to good yields under relatively mild reaction conditions. This approach is cheap, as using one of the cheapest transition metals, a simple protocol and various functional group tolerance make it a valuable strategy for getting -substituted furanose-fused OZT. The structures of the novel carbohydrates were confirmed by NMR spectroscopy and an HRMS analysis.
Topics: Catalysis; Copper; Iodides; Molecular Structure; Oxazoles; Thiones
PubMed: 36080364
DOI: 10.3390/molecules27175597