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International Journal of Molecular... Sep 2022Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies,...
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide () or hydrazone (-) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-]pyrrole derivative was a strong inhibitor of the TET1 protein (IC = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-]pyrroles -, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.
Topics: DNA; Dioxygenases; Hydrazones; Iron; Iron Chelating Agents; Mitochondrial Proteins; Molecular Docking Simulation; Pyrroles
PubMed: 36142763
DOI: 10.3390/ijms231810850 -
Journal of the American Chemical Society Dec 2023The structural analysis of guest molecules in rationally designed and self-assembling DNA crystals has proven an elusive goal since its conception. Oligonucleotide...
The structural analysis of guest molecules in rationally designed and self-assembling DNA crystals has proven an elusive goal since its conception. Oligonucleotide frameworks provide an especially attractive route toward studying DNA-binding molecules by using three-dimensional lattices with defined sequence and structure. In this work, we site-specifically position a suite of minor groove binding molecules, and solve their structures via X-ray crystallography as a proof-of-principle toward scaffolding larger guest species. Two crystal motifs were used to precisely immobilize the molecules DAPI, Hoechst, and netropsin at defined positions in the lattice, allowing us to control occupancy within the crystal. We also solved the structure of a three-ring imidazole-pyrrole-pyrrole polyamide molecule, which sequence-specifically packs in an antiparallel dimeric arrangement within the minor groove. Finally, we engineered a crystal designed to position both netropsin and the polyamide at two distinct locations within the same lattice. Our work elucidates the design principles for the spatial arrangement of functional guests within lattices and opens new potential opportunities for the use of DNA crystals to display and structurally characterize small molecules, peptides, and ultimately proteins of unknown structure.
Topics: Netropsin; Nylons; DNA; Oligonucleotides; Pyrroles; Nucleic Acid Conformation
PubMed: 37987645
DOI: 10.1021/jacs.3c07802 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2021Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as...
Hairpin pyrrole-imidazole polyamides (hPIPs) and their chlorambucil (Chb) conjugates (hPIP-Chbs) can alkylate DNA in a sequence-specific manner, and have been studied as anticancer drugs. Here, we conjugated Chb to a cyclic PIP (cPIP), which is known to have a higher binding affinity than the corresponding hPIP, and investigated the DNA alkylation properties of the resulting cPIP-Chb using the optimized capillary electrophoresis method and conventional HPLC product analysis. cPIP-Chb conjugate 3 showed higher alkylation activity at its binding sites than did hPIP-Chb conjugates 1 and 2. Subsequent HPLC analysis revealed that the alkylation site of conjugate 3, which was identified by capillary electrophoresis, was reliable and that conjugate 3 alkylates the N3 position of adenine as do hPIP-Chbs. Moreover, conjugate 3 showed higher cytotoxicity against LNCaP prostate cancer cells than did conjugate 1 and cytotoxicity comparable to that of conjugate 2. These results suggest that cPIP-Chbs could be novel DNA alkylating anticancer drugs.
Topics: Alkylation; Chlorambucil; DNA; Imidazoles; Nylons; Pyrroles
PubMed: 33145851
DOI: 10.1002/chem.202004421 -
International Journal of Molecular... Jun 2023The instability and volatility of iodine is high, however, effective iodine biocidal species can be readily stored in iodinated azoles and then be released upon...
The instability and volatility of iodine is high, however, effective iodine biocidal species can be readily stored in iodinated azoles and then be released upon decomposition or detonation. Iodine azoles with high iodine content and high thermal stability are highly desired. In this work, the strategy of methylene bridging with asymmetric structures of 3,4,5-triiodo-1-H-pyrazole (TIP), 2,4,5-triiodo-1H-imidazol (TIM), and tetraiodo-1H-pyrrole (TIPL) are proposed. Two highly stable fully iodinated methylene-bridged azole compounds 3,4,5-triiodo-1-((2,4,5-triiodo-1H-imidazol-1-yl)methyl)-1H-pyrazole () and 3,4,5-triiodo-1-((tetraiodo-1H-pyrrol-1-yl)methyl)-1H-pyrazole () were obtained with high iodine content and excellent thermal stability (iodine content: 84.27% for compound and 86.48% for compound ; T: : 285 °C, : 260 °C). Furthermore, their composites with high-energy oxidant ammonium perchlorate (AP) were designed. The combustion behavior and thermal decomposition properties of the formulations were tested and evaluated. This work may open a new avenue to develop advanced energetic biocidal materials with well-balanced energetic and biocidal properties and versatile functionality.
Topics: Azoles; Iodine; Pyrroles; Chemical Phenomena; Pyrazoles
PubMed: 37445889
DOI: 10.3390/ijms241310711 -
Journal of Medicinal Chemistry Aug 2022In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The...
Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.
In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC > 64 μg/mL). Compound displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K channel, and good efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against expressing wild-type and mutated variants of the gene from () and determining their effect on mycolic acid biosynthesis using a [C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.
Topics: Antitubercular Agents; Bacterial Proteins; Humans; Membrane Proteins; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrroles; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant
PubMed: 35915958
DOI: 10.1021/acs.jmedchem.2c00718 -
Carbene-catalyzed chemoselective reaction of unsymmetric enedials for access to Furo[2,3-b]pyrroles.Nature Communications Jul 2023A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in...
A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in excellent selectivity. A main challenge in this reaction is chemoselective reaction of the two aldehyde moieties in the enedial substrates. Mechanistic studies via experiments suggest that our chemoselectivity controls are mostly achieved on the reducing properties of different sited Breslow intermediates. Several side reactions processes and the corresponding side adducts are also studied by high resolution mass spectroscopy analysis. Our method allows for efficient assembly of the furo[2,3-b]pyrrole structural moieties and their analogues widely found in natural products and pharmaceuticals.
Topics: Molecular Structure; Pyrroles; Methane; Catalysis
PubMed: 37454112
DOI: 10.1038/s41467-023-39988-z -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2009In an effort to establish new pyrroles and pyrrolo[2,3-d] pyrimidines with improved antimicrobial activity we report here the synthesis and in vitro microbiological...
In an effort to establish new pyrroles and pyrrolo[2,3-d] pyrimidines with improved antimicrobial activity we report here the synthesis and in vitro microbiological evaluation of a series of pyrrole derivatives. A series of new 2-aminopyrrole-3-carbonitriles (1a-d) were synthesized from the reaction of benzoin, primary aromatic amines and malononitrile, from which a number of pyrrole derivatives (2a-d to 5a-d) and pyrrolo[2,3-d]pyrimidines (6a-d to 10a, d) were synthesized. The in vitro antimicrobial testing of the synthesized compounds was carried out against Gram-positive, Gram-negative bacteria and fungi. Some of the prepared compounds, [2-amino-1-(2-methylphenyl)-4,5-diphenyl-1H-pyrrole-3-carbonitriles (1b), 2-amino-3-carbamoyl-1-(3-methylphenyl)-4,5-diphenyl-1H-pyrroles (2b), N-(3-cyano-1-(2-methylphenyl)-4,5-diphenyl-1H-pyrrol-2-yl)-acetamides (3b), N-(3-cyano-1-(3-methylphenyl)-4,5-diphenyl-1H-pyrrol-2-yl)-acetamides (3c), 2-amino-1-(4-methoxyphenyl)-4,5-diphenyl-3-tetrazolo-1H-pyrroles (5d), 7-(4-methoxyphenyl)-5,6-diphenyl-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-ones (7d), 7-(3-methylphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-thione (9b) and N-(7-(2-methylphenyl)-5,6-diphenyl-7H-pyrrolo[2,3-d] pyrimidine)-N-aryl amines (10a)] showed potent antimicrobial activity.
Topics: Anti-Infective Agents; Drug Design; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Structure; Pyrimidines; Pyrroles; Structure-Activity Relationship
PubMed: 19564140
DOI: 10.2478/v10007-009-0016-9 -
Angewandte Chemie (International Ed. in... Jul 2021The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity....
The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity. Multiconfigurational quantum chemical computations disclose the mechanism for this spin-forbidden process. Despite a negligible spin-orbit coupling constant, the intersystem crossing (ISC) is facilitated by singlet and triplet state degeneracy and spin-vibronic coupling. The formed peroxides are stable toward external substrates but undergo an unprecedented oxidative pyrrole α-cleavage by ligand aromatization/dearomatization-initiated O-O σ-bond scission. A detailed comparison of the calix[4]pyrrolato aluminates with dioxygen-related enzymology provides insights into the ISC of metal- or cofactor-free enzymes. It substantiates the importance of structural constraint and element-ligand cooperativity for the functions of aerobic life.
Topics: Aluminum; Calixarenes; Density Functional Theory; Flavoproteins; Models, Molecular; Molecular Structure; Oxygen; Phenols; Pyrroles
PubMed: 33955154
DOI: 10.1002/anie.202104916 -
Journal of Natural Products Apr 2019Three new pyoluteorin analogues, mindapyrroles A-C (1-3), were purified from Pseudomonas aeruginosa strain 1682U.R.0a.27, a gill-associated bacterium isolated from the...
Three new pyoluteorin analogues, mindapyrroles A-C (1-3), were purified from Pseudomonas aeruginosa strain 1682U.R.0a.27, a gill-associated bacterium isolated from the tissue homogenate of the giant shipworm Kuphus polythalamius. Mindapyrroles B and C inhibit the growth of multiple pathogenic bacteria, with mindapyrrole B (2) showing the most potent antimicrobial activity and widest selectivity index over mammalian cells. Preliminary structure-activity relationship analysis showed that dimerization of the pyoluteorin moiety through a C-C linkage is detrimental to the antimicrobial activity, but addition of an aerugine unit in the methylene bridge is favorable for both the antimicrobial activity and selectivity index.
Topics: Animals; Anti-Infective Agents; Bivalvia; Pseudomonas aeruginosa; Pyrroles
PubMed: 30793902
DOI: 10.1021/acs.jnatprod.8b00979 -
Chemical Communications (Cambridge,... Aug 2014The pyrrole-imidazole alkaloids are a group of structurally unique and biologically interesting marine sponge metabolites. Among them, the cyclic dimers have caught... (Review)
Review
The pyrrole-imidazole alkaloids are a group of structurally unique and biologically interesting marine sponge metabolites. Among them, the cyclic dimers have caught synthetic chemists' attention particularly. Numerous synthetic strategies have been developed and various biosynthetic hypotheses have been proposed for these fascinating natural products. We discuss herein the synthetic approaches and the biosynthetic insights obtained from these studies.
Topics: Alkaloids; Animals; Biological Products; Imidazoles; Porifera; Pyrroles
PubMed: 24828265
DOI: 10.1039/c4cc02290d