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Journal of the American Chemical Society Mar 2006Inhibiting the enzyme telomerase by stabilizing the G-quadruplex has potential in anticancer drug design. Diprotonated cyclo[n]pyrroles represent a set of expanded...
Inhibiting the enzyme telomerase by stabilizing the G-quadruplex has potential in anticancer drug design. Diprotonated cyclo[n]pyrroles represent a set of expanded porphyrin analogues with structures similar to that of telomestatin, a natural product known to bind to and stabilize G-quadruplexes. As a first step toward testing whether cyclo[n]pyrroles display a similar function, a series of diprotonated cyclo[n]pyrroles (where n = 6, 7, and 8) was each added to the human telomere repeat sequence d(T(2)AG(3))(4) and examined with mass spectrometry, ion mobility, and molecular dynamics calculations. Nano-ESI-MS indicated that the smaller the cyclo[n]pyrrole, the more strongly it binds to the telomeric sequence. It was also found that cyclo[6]pyrrole bound to d(T(2)AG(3))(4) better than octaethylporphyrin, a finding rationalized by cyclo[6]pyrrole having a 2+ charge, while octaethylporphyrin bears no charge. Ion mobility measurements were used to measure the collision cross section of each d(T(2)AG(3))(4)/cyclo[n]pyrrole complex. Only one peak was observed in the arrival time distributions for all complexes, and the experimental cross sections indicated that only structures with d(T(2)AG(3))(4) in an antiparallel G-quadruplex arrangement and each cyclo[n]pyrrole externally stacked below the G-quartets occur under these experimental conditions. When the cyclo[n]pyrroles were intercalated or nonspecifically bound to the quadruplex, or if conformations different than antiparallel were considered for d(T(2)AG(3))(4), the theoretical cross sections did not match experiment. On this basis, it is inferred that (1) external stacking represents the dominant binding mode for the interaction of cyclo[n]pyrroles with d(T(2)AG(3))(4) and (2) the overall size and charge of the cyclo[n]pyrroles play important roles in defining the binding strength.
Topics: Binding Sites; DNA; Enzyme Inhibitors; G-Quadruplexes; Guanine; Models, Molecular; Nucleic Acid Conformation; Porphyrins; Pyrroles; Spectrometry, Mass, Electrospray Ionization; Substrate Specificity; Telomerase; Thermodynamics
PubMed: 16492050
DOI: 10.1021/ja0564968 -
Biochemistry Feb 2018The G-quadruplex (G4) is one type of higher-order structure of nucleic acids and is thought to play important roles in various biological events such as regulation of...
The G-quadruplex (G4) is one type of higher-order structure of nucleic acids and is thought to play important roles in various biological events such as regulation of transcription and inhibition of DNA replication. Pyrrole-imidazole polyamides (PIPs) are programmable small molecules that can sequence-specifically bind with high affinity to the minor groove of double-stranded DNA (dsDNA). Herein, we designed head-to-head hairpin PIP dimers and their target dsDNA in a model G4-forming sequence. Using an electrophoresis mobility shift assay and transcription arrest assay, we found that PIP dimers could induce the structural change to G4 DNA from dsDNA through the recognition by one PIP dimer molecule of two duplex-binding sites flanking both ends of the G4-forming sequence. This induction ability was dependent on linker length. This is the first study to induce G4 formation using PIPs, which are known to be dsDNA binders. The results reported here suggest that selective G4 induction in native sequences may be achieved with PIP dimers by applying the same design strategy.
Topics: Base Sequence; Binding Sites; DNA; Dimerization; G-Quadruplexes; Imidazoles; Models, Molecular; Nylons; Pyrroles
PubMed: 29236465
DOI: 10.1021/acs.biochem.7b01059 -
Molecules (Basel, Switzerland) Oct 2021A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new...
A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new tri- and tetra-substituted -arylpyrroles were synthesized by the one-pot reaction of 1-methyl-3-cyanomethyl benzimidazolium bromide with substituted alkynes having at least one electron-withdrawing substituent, in 1,2-epoxybutane, acting both as the solvent and reagent to generate the corresponding benzimidazolium N3-ylide. The structural characterization of the new substituted pyrroles was based on IR, NMR spectroscopy as well as on single crystal X-ray analysis. The toxicity of the new compounds was assessed on the plant cell using L. species and on the animal cell using Kellogg and Straus crustaceans. The compounds showed minimal phytotoxicity on rootlets and virtually no acute toxicity on nauplii, while on , it induced moderate to high toxicity, similar to nifedipine. Our research indicates that the newly synthetized pyrrole derivatives are promising molecules with biological activity and low acute toxicity.
Topics: Alkynes; Benzimidazoles; Bromides; Chemistry Techniques, Synthetic; Models, Molecular; Molecular Structure; Pyrroles; Spectrum Analysis; Toxicity Tests; Toxicology
PubMed: 34770844
DOI: 10.3390/molecules26216435 -
Molecules (Basel, Switzerland) Mar 2022Described in this paper are studies on the preparation of three classes of dimethylpyridinols derived from pyridoxine fused with aminooxazole, aminoimidazole, and...
Described in this paper are studies on the preparation of three classes of dimethylpyridinols derived from pyridoxine fused with aminooxazole, aminoimidazole, and aminopyrrole. The key feature of this synthetic strategy is the manipulation of hydroxymethyl moiety of C(5)-position of the pyridoxine starting material along with the installation of an amino group at C(6)-position. Efficient and practical synthesis for the oxazole- and imidazole-fused targets was accomplished, while the instability of the pyrrole-fused one was observed.
Topics: Oxazoles; Pyridoxine; Pyrroles
PubMed: 35408475
DOI: 10.3390/molecules27072075 -
Molecules (Basel, Switzerland) Nov 2019This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of... (Review)
Review
This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of pyrroles and aldehydes or ketones, and recent breakthroughs which allow the synthesis of these type of heterocycles with new substitution patterns.
Topics: Aldehydes; Catalysis; Chemistry Techniques, Synthetic; Hydrochloric Acid; Indium; Molecular Structure; Pyrroles
PubMed: 31795117
DOI: 10.3390/molecules24234348 -
ACS Chemical Biology Apr 2020Anthelvencins A and B are pyrrolamide metabolites produced by ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate...
Anthelvencins A and B are pyrrolamide metabolites produced by ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate antibacterial activities. In this study, we revise the structure of anthelvencin A and identify a third anthelvencin metabolite, bearing two -methylated pyrrole groups, which we named anthelvencin C. We sequenced the genome of ATCC 14583 and identified a gene cluster predicted to direct the biosynthesis of anthelvencins. Functional analysis of this gene cluster confirmed its involvement in anthelvencin biosynthesis and allowed us to propose a biosynthetic pathway for anthelvencins. In addition to a nonribosomal peptide synthetase (NRPS), the assembly of anthelvencins involves an enzyme from the ATP-grasp ligase family, Ant23. We propose that Ant23 uses a PCP-loaded 4-aminopyrrole-2-carboxylate as substrate. As observed for the biosynthesis of the other pyrrolamides congocidine (produced by ATCC 25877) and distamycin (produced by DSM 40846), the NRPS assembling anthelvencins is composed of stand-alone domains only. Such NRPSs, sometimes called type II NRPSs, are less studied than the classical multimodular NRPSs. Yet, they constitute an interesting model to study protein-protein interactions in NRPSs and are good candidates for combinatorial biosynthesis approaches.
Topics: Bacterial Proteins; Multigene Family; Peptide Synthases; Protein Domains; Pyrroles; Streptomyces
PubMed: 32129986
DOI: 10.1021/acschembio.9b00960 -
International Journal For Parasitology.... Dec 2019Subversion of parasite neuromuscular function is a key strategy for anthelmintic drug development. Schistosome Ca signaling has been an area of particular interest for...
Subversion of parasite neuromuscular function is a key strategy for anthelmintic drug development. Schistosome Ca signaling has been an area of particular interest for decades, with a specific focus on L-type voltage-gated Ca channels (Cas). However, the study of these channels has been technically challenging. One barrier is the lack of pharmacological probes that are active on flatworms, since the dihydropyridine (DHP) based ligands typically used to study Cas are relatively ineffective on schistosomes. Here, we have characterized the effect of a structurally distinct putative L-type Ca agonist, FPL-64176, on schistosomes cultured ex vivo and in an in vivo murine model of infection. Unlike DHPs, FPL-64176 evokes rapid and sustained contractile paralysis of adult Schistosoma mansoni reminiscent of the anthelmintic praziquantel. This is accompanied by tegument disruption and an arrest of mitotic activity in somatic stem cells and germ line tissues. Interestingly, this strong ex vivo phenotype was temperature dependent, with FPL-64176 treatment being less potent at 37 °C than 23 °C. However, FPL-64176 caused intra-tegument lesions at the basement membrane of worms cultured ex vivo under both conditions, as well as an in vivo hepatic shift of parasites from the mesenteric vasculature of infected mice to the liver. Gene expression profiling of worms harvested following in vivo FPL-64176 exposure reveals differences in transcripts associated with muscle and extracellular matrix function, as well as female reproduction, which is consistent with the worm phenotypes observed following ex vivo drug treatment. These data advance FPL-64176 as a useful tool to study schistosome Ca signaling, and the benzoyl pyrrole core as a hit compound that may be optimized to develop new parasite-selective leads.
Topics: Animals; Biotinylation; Calcium Channel Agonists; Calcium Signaling; Female; Helminth Proteins; Male; Mice; Microscopy, Electron, Transmission; Pyrroles; Real-Time Polymerase Chain Reaction; Schistosoma mansoni; Schistosomiasis mansoni
PubMed: 31561039
DOI: 10.1016/j.ijpddr.2019.08.006 -
International Journal of Molecular... Aug 2022The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new...
The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, H-NMR and C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., L.) and animal cells using aquatic crustaceans (i.e., Kellogg and Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on L., while on Kellogg nauplii, only compounds and had moderate toxicity. On , and showed high toxicity; , , and moderate to high toxicity; only and were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by and its homologue , especially against LoVo colon cells.
Topics: Animals; Antineoplastic Agents; Biological Factors; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Endothelial Cells; Female; Humans; Molecular Structure; Pyrroles; Structure-Activity Relationship
PubMed: 36012121
DOI: 10.3390/ijms23168854 -
Marine Drugs Dec 2014The present review discusses the known synthetic routes to the lamellarin alkaloids published until 2014. It begins with syntheses of the structurally simpler type-II... (Review)
Review
The present review discusses the known synthetic routes to the lamellarin alkaloids published until 2014. It begins with syntheses of the structurally simpler type-II lamellarins and then focuses on the larger class of the 5,6-saturated and -unsaturated type-I lamellarins. The syntheses are grouped by the strategy employed for the assembly of the central pyrrole ring.
Topics: Alkaloids; Coumarins; Heterocyclic Compounds, 4 or More Rings; Pyrroles
PubMed: 25528958
DOI: 10.3390/md12126142 -
Biochimica Et Biophysica Acta. General... Sep 2018Human porphobilinogen deaminase (PBGD), the third enzyme in the heme pathway, catalyzes four times a single reaction to convert porphobilinogen into hydroxymethylbilane....
Human porphobilinogen deaminase (PBGD), the third enzyme in the heme pathway, catalyzes four times a single reaction to convert porphobilinogen into hydroxymethylbilane. Remarkably, PBGD employs a single active site during the process, with a distinct yet chemically equivalent bond formed each time. The four intermediate complexes of the enzyme have been biochemically validated and they can be isolated but they have never been structurally characterized other than the apo- and holo-enzyme bound to the cofactor. We present crystal structures for two human PBGD intermediates: PBGD loaded with the cofactor and with the reaction intermediate containing two additional substrate pyrrole rings. These results, combined with SAXS and NMR experiments, allow us to propose a mechanism for the reaction progression that requires less structural rearrangements than previously suggested: the enzyme slides a flexible loop over the growing-product active site cavity. The structures and the mechanism proposed for this essential reaction explain how a set of missense mutations result in acute intermittent porphyria.
Topics: Catalysis; Catalytic Domain; Crystallography, X-Ray; Humans; Hydroxymethylbilane Synthase; Polymerization; Porphobilinogen; Protein Conformation; Pyrroles; Uroporphyrinogens
PubMed: 29908816
DOI: 10.1016/j.bbagen.2018.06.013