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Chemical Record (New York, N.Y.) Jun 2021To maintain the functions of living organisms, cells have developed complex gene regulatory networks. Transcription factors have a central role in spatiotemporal control... (Review)
Review
To maintain the functions of living organisms, cells have developed complex gene regulatory networks. Transcription factors have a central role in spatiotemporal control of gene expression and this has motivated us to develop artificial transcription factors that mimic their function. We found that three functions could be mimicked by applying our chemical approaches: i) efficient delivery into organelles that contain target DNA, ii) specific DNA binding to the target genomic region, and iii) regulation of gene expression by interaction with other transcription coregulators. We chose pyrrole-imidazole polyamides (PIPs), sequence-selective DNA binding molecules, as DNA binding domains, and have achieved each of the required functions by introducing other functional moieties. The developed artificial transcription factors have potential as chemical tools that can be used to artificially modulate gene expression to enable cell fate control and to correct abnormal gene regulation for therapeutic purposes.
Topics: DNA; Humans; Imidazoles; Nylons; Pyrroles; Transcription Factors
PubMed: 33332727
DOI: 10.1002/tcr.202000158 -
Analytical Sciences : the International... 2010A series of N-substituted pyrroles having phosphorylcholine with different methylene chain lengths between pyrrole group and phosphorylcholine group were synthesized and...
A series of N-substituted pyrroles having phosphorylcholine with different methylene chain lengths between pyrrole group and phosphorylcholine group were synthesized and their electropolymerizations were performed in aqueous solution. The methylene chains were trimethylene (n = 3), pentamethylene (n = 5), nonamethylene (n = 9), and undecamethylene (n = 11), for 3-(1-pyrrolyl)propyl-2-(trimethylammonium)ethyl phosphate (5a), 5-(1-pyrrolyl)pentyl-2-(trimethylammonium)ethyl phosphate (5b), 9-(1-pyrrolyl)nonyl-2-(trimethylammonium)ethyl phosphate (5c), and 11-(1-pyrrolyl)undecyl-2-(trimethylammonium)ethyl phosphate (5d), respectively. Although electropolymerized films were produced from all pyrrole derivatives, thick and black polymer films were prepared from 5a, 5b and 5c. The pyrrole derivative with long methylene-chain 5d provided only colorless or slightly blackish thin film. Hemocompatibilities of the polymers from 5a, 5b and 5c were evaluated by platelet rich plasma (PRP) contacting studies and scanning electron microscopy (SEM) observations. The results indicated that these polymers have excellent hemocompatibility.
Topics: Biocompatible Materials; Blood; Blood Coagulation; Electrochemistry; Humans; Methane; Microscopy, Electron, Scanning; Phosphorylcholine; Platelet-Rich Plasma; Polymers; Pyrroles; Solutions; Water
PubMed: 20467127
DOI: 10.2116/analsci.26.539 -
Journal of the American Chemical Society Jan 2024Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent...
Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent antioxidant, oxidative transformations of bilirubin occur in vivo and lead to various oxidized fragments. The mechanisms of their formation, intrinsic biological activities, and potential roles in human pathophysiology are poorly understood. Degradation methods have been used to obtain samples of bilirubin oxidation products for research. Here, we report a complementary, fully synthetic method of preparation. Our strategy leverages repeating substitution patterns in the parent tetracyclic pigment. Functionalized ready-to-couple γ-lactone, γ-lactam, and pyrrole monocyclic building blocks were designed and efficiently synthesized. Subsequent modular combinations, supported by metal-catalyzed borylation and cross-coupling chemistries, translated into the concise assembly of the structurally diverse bilirubin oxidation products (BOXes, propentdyopents, and biopyrrins). The discovery of a new photoisomer of biopyrrin A named lumipyrrin is reported. Synthetic bilirubin oxidation products made available in sufficient purity and quantity will support future in vitro and in vivo investigations.
Topics: Humans; Bilirubin; Oxidation-Reduction; Pyrroles; Oxidative Stress
PubMed: 38165253
DOI: 10.1021/jacs.3c11778 -
Biochemical Pharmacology Oct 2017Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics...
Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoyl-5-(2,5-dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists.
Topics: Anti-Inflammatory Agents; Binding, Competitive; Calcium; Cell Adhesion; Cell Culture Techniques; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Neutrophils; Pyrroles; Receptors, Formyl Peptide; Structure-Activity Relationship; Transfection
PubMed: 28690139
DOI: 10.1016/j.bcp.2017.07.004 -
Marine Drugs Oct 2013Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl... (Review)
Review
Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl groups. To date, there are approximately 30 naturally occurring dithiolopyrrolone compounds, including holomycin, thiolutin, and aureothricin, and more recently thiomarinols, a unique class of hybrid marine bacterial natural products containing a dithiolopyrrolone framework linked by an amide bridge with an 8-hydroxyoctanoyl chain linked to a monic acid. Generally, dithiolopyrrolone antibiotics have broad-spectrum antibacterial activity against various microorganisms, including Gram-positive and Gram-negative bacteria, and even parasites. Holomycin appeared to be active against rifamycin-resistant bacteria and also inhibit the growth of the clinical pathogen methicillin-resistant Staphylococcus aureus N315. Its mode of action is believed to inhibit RNA synthesis although the exact mechanism has yet to be established in vitro. A recent work demonstrated that the fish pathogen Yersinia ruckeri employs an RNA methyltransferase for self-resistance during the holomycin production. Moreover, some dithiolopyrrolone derivatives have demonstrated promising antitumor activities. The biosynthetic gene clusters of holomycin have recently been identified in S. clavuligerus and characterized biochemically and genetically. The biosynthetic gene cluster of thiomarinol was also identified from the marine bacterium Pseudoalteromonas sp. SANK 73390, which was uniquely encoded by two independent pathways for pseudomonic acid and pyrrothine in a novel plasmid. The aim of this review is to give an overview about the isolations, characterizations, synthesis, biosynthesis, bioactivities and mode of action of this unique family of dithiolopyrrolone natural products, focusing on the period from 1940s until now.
Topics: Anti-Bacterial Agents; Bacteria; Biological Products; Humans; Lactams; Mupirocin; Pyrroles; Pyrrolidinones; Sulfhydryl Compounds
PubMed: 24141227
DOI: 10.3390/md11103970 -
Saudi Journal of Gastroenterology :... 2017
Topics: Amoxicillin; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Male; Omeprazole; Proton Pump Inhibitors; Pyrroles; Stomach; Sulfonamides; Treatment Failure
PubMed: 28937019
DOI: 10.4103/sjg.SJG_292_17 -
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 -
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 -
Molecules (Basel, Switzerland) May 2016The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a... (Review)
Review
The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a comparatively small number of ring-containing structures. Pyrrole, indole, pyridine, quinoline, quinazoline and related 6-membered ring-containing aza-arenes figure prominently. This review focuses on the search for fast, efficient and environmentally friendly preparative methods for these rings with specific emphasis on iminyl radical-mediated procedures. Oxime derivatives, particularly oxime esters and oxime ethers, are attractive precursors for these radicals. Their use is described in conventional thermolytic, microwave-assisted and UV-vis based preparative procedures. Photoredox-catalyzed protocols involving designer oxime ethers are also covered. Choice can be made amongst these synthetic strategies for a wide variety of 5- and 6-membered ring heterocycles including phenanthridine and related aza-arenes. Applications to selected natural products and bioactive molecules, including trispheridine, vasconine, luotonin A and rutaecarpine, are included.
Topics: Catalysis; Cyclization; Dioxoles; Free Radicals; Indole Alkaloids; Oximes; Phenanthridines; Pyridines; Pyrroles; Quinazolines; Quinones
PubMed: 27213311
DOI: 10.3390/molecules21050660 -
International Journal of Molecular... Jan 2021In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides -. The compounds - were...
In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides -. The compounds - were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-]pyrrole scaffold (-) with secondary amines and an excess of formaldehyde solution in CHOH. The structural properties of the compounds were characterized by H NMR, C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound . The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.
Topics: Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Drug Design; Enzyme Assays; Humans; Imides; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Molecular Structure; Pyrroles; Structure-Activity Relationship
PubMed: 33573356
DOI: 10.3390/ijms22031410