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Chemistry (Weinheim An Der Bergstrasse,... Jan 2022Oxidation of the iron(II) precursor [(L )Fe Cl ], where L is a tetradentate bispidine, with soluble iodosylbenzene ( PhIO) leads to the extremely reactive ferryl oxidant...
Oxidation of the iron(II) precursor [(L )Fe Cl ], where L is a tetradentate bispidine, with soluble iodosylbenzene ( PhIO) leads to the extremely reactive ferryl oxidant [(L )(Cl)Fe =O] with a cis disposition of the chlorido and oxido coligands, as observed in non-heme halogenase enzymes. Experimental data indicate that, with cyclohexane as substrate, there is selective formation of chlorocyclohexane, the halogenation being initiated by C-H abstraction and the result of a rebound of the ensuing radical to an iron-bound Cl . The time-resolved formation of the halogenation product indicates that this primarily results from PhIO oxidation of an initially formed oxido-bridged diiron(III) resting state. The high yield of up to >70 % (stoichiometric reaction) as well as the differing reactivities of free Fe and Fe in comparison with [(L )Fe Cl ] indicate a high complex stability of the bispidine-iron complexes. DFT analysis shows that, due to a large driving force and small triplet-quintet gap, [(L )(Cl)Fe =O] is the most reactive small-molecule halogenase model, that the Fe /radical rebound intermediate has a relatively long lifetime (as supported by experimentally observed cage escape), and that this intermediate has, as observed experimentally, a lower energy barrier to the halogenation than the hydroxylation product; this is shown to primarily be due to steric effects.
Topics: Carbon; Ferric Compounds; Halogenation; Hydrogen Bonding; Iron
PubMed: 34792224
DOI: 10.1002/chem.202103452 -
Ecotoxicology and Environmental Safety Apr 2022Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) are highly toxic and persistent compounds that provoke a wave of publicity. Bromophenols are important...
Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) are highly toxic and persistent compounds that provoke a wave of publicity. Bromophenols are important precursors for forming PBDD/Fs, and their reaction path has always been a research hotspot. In this study, the formation characteristic of PBDD/Fs from 2,4,6-TBP were studied. The yields of 2,3,7,8-substituted PBDD/Fs and 2,4,6,8-TBDF for the different thermal products ranged from 0.067 to 10.3 ng/g and 0.207-9.68 ng/g, respectively. The effects of adding Cu, Fe, and SbO were investigated and found to be more inclined to accelerate the formation of ortho-substituted PBDD/Fs than 2,3,7,8-PBDD/Fs. The formation pathways of 2,3,7,8-substituted PBDD/Fs and 2,4,6,8-TBDF were also proposed. 2,4,6,8-TBDF is generated in the C-C coupling reactions of some radical intermediates from the debromination of 2,4,6-TBP. The 2,3,7,8-PBDD/Fs are produced through more complex debromination, bromine substitution, and bromine rearrangement reactions. In addition, various catalytic effects on PBDD/F formation pathways were found, and the catalytic effect of Cu by the Ullmann reaction was the highest, while bromophenol oxidation by Fe was the highest. These results proved that both 2,3,7,8-substituted and non-2,3,7,8-substituted PBDD/Fs would be generated from 2,4,6-TBP, and the effects of the catalyst on the Br substituted position of 2,3,7,8-substituted PBDD/Fs were much lower than the Br-substituted position on bromophenol.
Topics: Bromine; Dibenzofurans; Phenols
PubMed: 35358919
DOI: 10.1016/j.ecoenv.2022.113449 -
Bioorganic & Medicinal Chemistry Letters Jun 2018Halogenation is commonly used in medicinal chemistry to improve the potency of pharmaceutical leads. While synthetic methods for halogenation present selectivity and... (Review)
Review
Halogenation is commonly used in medicinal chemistry to improve the potency of pharmaceutical leads. While synthetic methods for halogenation present selectivity and reactivity challenges, halogenases have evolved over time to perform selective reactions under benign conditions. The optimization of halogenation biocatalysts has utilized enzyme evolution and structure-based engineering alongside biotransformation in a variety of systems to generate stable site-selective variants. The recent improvements in halogenase-catalyzed reactions has demonstrated the utility of these biocatalysts for industrial purposes, and their ability to achieve a broad substrate scope implies a synthetic tractability with increasing relevance in medicinal chemistry.
Topics: Chemistry, Pharmaceutical; Halogenation; Oxidoreductases; Protein Engineering
PubMed: 29731363
DOI: 10.1016/j.bmcl.2018.04.066 -
Acta Crystallographica. Section D,... Mar 2016Heavy-atom derivatization is one of the oldest techniques for obtaining phase information for protein crystals and, although it is no longer the first choice, it remains... (Review)
Review
Heavy-atom derivatization is one of the oldest techniques for obtaining phase information for protein crystals and, although it is no longer the first choice, it remains a useful technique for obtaining phases for unknown structures and for low-resolution data sets. It is also valuable for confirming the chain trace in low-resolution electron-density maps. This overview provides a summary of the technique and is aimed at first-time users of the method. It includes guidelines on when to use it, which heavy atoms are most likely to work, how to prepare heavy-atom solutions, how to derivatize crystals and how to determine whether a crystal is in fact a derivative.
Topics: Animals; Bromine; Crystallography, X-Ray; Humans; Iodine; Metals, Heavy; Methionine; Noble Gases; Protein Conformation; Proteins; Selenomethionine
PubMed: 26960118
DOI: 10.1107/S2059798316000401 -
Water Research Dec 2020Hypochlorous acid (HOCl) is typically assumed to be the primary reactive species in free available chlorine (FAC) solutions. Lately, it has been shown that less abundant...
Hypochlorous acid (HOCl) is typically assumed to be the primary reactive species in free available chlorine (FAC) solutions. Lately, it has been shown that less abundant chlorine species such as chlorine monoxide (ClO) and chlorine (Cl) can also influence the kinetics of the abatement of certain organic compounds during chlorination. In this study, the chlorination as well as bromination kinetics and mechanisms of 12 olefins (including 3 aliphatic and 9 aromatic olefins) with different structures were explored. HOCl shows a low reactivity towards the selected olefins with species-specific second-order rate constants <1.0 Ms, about 4-6 orders of magnitude lower than those of ClO and Cl. HOCl is the dominant chlorine species during chlorination of olefins under typical drinking water conditions, while ClO and Cl are likely to play important roles at high FAC concentration near circum-neutral pH (for ClO) or at high Cl concentration under acidic conditions (for Cl). Bromination of the 12 olefins suggests that HOBr and BrO are the major reactive species at pH 7.5 with species-specific second-order rate constants of BrO nearly 3-4 orders of magnitude higher than of HOBr (ranging from <0.01 to >10 Ms). The reactivities of chlorine and bromine species towards olefins follow the order of HOCl < HOBr < BrO < ClO ≈ Cl. Generally, electron-donating groups (e.g., CHOH- and CH-) enhances the reactivities of olefins towards chlorine and bromine species by a factor of 3-10, while electron-withdrawing groups (e.g., Cl-, Br-, NO-, COOH-, CHO-, -COOR, and CN-) reduce the reactivities by a factor of 3-10. A reasonable linear free energy relationship (LFER) between the species-specific second-order rate constants of BrO or ClO reactions with aromatic olefins and their Hammett σ was established with a more negative ρ value for BrO than for ClO, indicating that BrO is more sensitive to substitution effects. Chlorinated products including HOCl-adducts and decarboxylated Cl-adduct were identified during chlorination of cinnamic acid by high-performance liquid chromatography/high resolution mass spectrometry (HPLC/HRMS).
Topics: Alkenes; Chlorine; Halogenation; Kinetics; Water Purification
PubMed: 33038657
DOI: 10.1016/j.watres.2020.116424 -
Journal of the American Chemical Society Nov 2020Ruppert-Prakash type reagents (TMSCF, TMSCF, and TMSCF) are readily available, air-stable, and easy-to-handle fluoroalkyl sources. Herein, we describe a mild,...
Ruppert-Prakash type reagents (TMSCF, TMSCF, and TMSCF) are readily available, air-stable, and easy-to-handle fluoroalkyl sources. Herein, we describe a mild, copper-catalyzed cross-coupling of these fluoroalkyl nucleophiles with aryl and alkyl bromides to produce a diverse array of trifluoromethyl, pentafluoroethyl, and heptafluoropropyl adducts. This light-mediated transformation proceeds via a silyl-radical-mediated halogen atom abstraction pathway, which enables perfluoroalkylation of a broad range of organobromides of variable steric and electronic demand. The utility of the method is demonstrated through the late-stage functionalization of several drug analogues.
Topics: Alkylation; Catalysis; Copper; Fluorocarbons; Halogenation; Hydrocarbons, Brominated; Oxidation-Reduction; Photochemical Processes; Silanes
PubMed: 33164534
DOI: 10.1021/jacs.0c09977 -
Scientific Reports Sep 2020Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic...
Antimicrobial peptides have attracted considerable interest as potential new class of antibiotics against multi-drug resistant bacteria. However, their therapeutic potential is limited, in part due to susceptibility towards enzymatic degradation and low bioavailability. Peptoids (oligomers of N-substituted glycines) demonstrate proteolytic stability and better bioavailability than corresponding peptides while in many cases retaining antibacterial activity. In this study, we synthesized a library of 36 peptoids containing fluorine, chlorine, bromine and iodine atoms, which vary by length and level of halogen substitution in position 4 of the phenyl rings. As we observed a clear correlation between halogenation of an inactive model peptoid and its increased antimicrobial activity, we designed chlorinated and brominated analogues of a known peptoid and its shorter counterpart. Short brominated analogues displayed up to 32-fold increase of the activity against S. aureus and 16- to 64-fold against E. coli and P. aeruginosa alongside reduced cytotoxicity. The biological effect of halogens seems to be linked to the relative hydrophobicity and self-assembly properties of the compounds. By small angle X-ray scattering (SAXS) we have demontrated how the self-assembled structures are dependent on the size of the halogen, degree of substitution and length of the peptoid, and correlated these features to their activity.
Topics: Anti-Bacterial Agents; Cell Line; Cell Survival; Escherichia coli; Halogenation; Humans; Microbial Sensitivity Tests; Peptoids; Pseudomonas aeruginosa; Scattering, Small Angle; Staphylococcus aureus
PubMed: 32908179
DOI: 10.1038/s41598-020-71771-8 -
Molecular Imaging and Biology Oct 2020CXCR4 is one of several "chemokine" receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although Ga-pentixafor and...
PURPOSE
CXCR4 is one of several "chemokine" receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although Ga-pentixafor and Ga-NOTA-NFB have been shown to effectively image CXCR4 expression in myeloma and other systemic malignancies, imaging CXCR4 expression in brain tumors has been more limited due to the blood-brain barrier (BBB) and a considerable fraction of CXCR4 staining is intracellular.
METHODS
We synthesized 6 iodinated and brominated cyclam derivatives with high affinity (low nM range) for CXCR4, since structure-based estimates of lipophilicity suggested rapid transfer across the BBB and tumor cell membranes.
RESULTS
We tested 3 iodinated and 3 brominated cyclam derivatives in several CXCR4(+) and CXCR4(-) cell lines, with and without cold ligand blocking. To validate these novel radiolabeled cyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial GBM and PCNSL. Based on initial studies, I-HZ262 and Br-HZ270-1 were shown to be the most avidly accumulated radioligands. Br-HZ270-1 was selected for further study in the U87-CXCR4 and PCNSL #15 intracranial tumor models, because of its high uptake (9.5 ± 1.3 %ID/g, SD) and low non-specific uptake (1.6 ± 0.7 %ID/g, SD) in the s.c. U87-CXCR4 tumor models. However, imaging CXCR4 expression in intracranial U87-CXCR4 and PCNSL #15 tumors with Br-HZ270-1 was unsuccessful, following either i.v. or spinal-CSF injection.
CONCLUSIONS
Imaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues-as reflected in the "measured" radiotracer distribution (LogD) in octanol/PBS-which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest BTB in intracranial U87-CXCR4 gliomas and an intact BBB/BTB in the intracranial PCNSL animal model.
Topics: Animals; Bromine; Cell Line, Tumor; Cyclams; Halogenation; Humans; Image Processing, Computer-Assisted; Iodine; Magnetic Resonance Imaging; Mice, Inbred C57BL; Mice, Nude; Positron-Emission Tomography; Receptors, CXCR4; Small Molecule Libraries; Tissue Distribution
PubMed: 32239371
DOI: 10.1007/s11307-020-01480-1 -
PloS One 2022The hadal amphipod Hirondellea gigas is an emblematic animal of the Pacific trenches, and has a number of special adaptations to thrive in this 'extreme' environment,...
The hadal amphipod Hirondellea gigas is an emblematic animal of the Pacific trenches, and has a number of special adaptations to thrive in this 'extreme' environment, which includes the deepest part of the Earth's ocean. One such adaptation that has been suggested is the presence of an 'aluminum gel shield' on the surface of its body in order to prevent the dissolution of calcitic exoskeleton below the carbonate compensation depth. However, this has not been investigated under experimental conditions that sufficiently prevent aluminum artefacts, and the possibility of other elements with similar characteristic X-ray energy as aluminum (such as bromine) has not been considered. Here, we show with new electron microscopy data gathered under optimized conditions to minimize aluminum artefacts that H. gigas actually does not have an aluminum shield-instead many parts of its body are enriched in bromine, particularly gastric ossicles and setae. Results from elemental analyses pointed to the use of calcite partially substituted with magnesium by H. gigas in its exoskeleton, in order to suppress dissolution. Our results exemplify the necessity of careful sample preparation and analysis of the signals in energy-dispersive X-ray spectroscopic analysis, and the importance of analyses at different electron energies.
Topics: Aluminum; Amphipoda; Animals; Bromine; Gizzard, Non-avian; Sensilla
PubMed: 35925928
DOI: 10.1371/journal.pone.0272032 -
Current Opinion in Chemical Biology Oct 2007The halogenation of thousands of natural products occurs during biosynthesis and often confers important functional properties. While haloperoxidases had been the... (Review)
Review
The halogenation of thousands of natural products occurs during biosynthesis and often confers important functional properties. While haloperoxidases had been the default paradigm for enzymatic incorporation of halogens, via X+ equivalents into organic scaffolds, a combination of microbial genome sequencing, enzymatic studies and structural biology have provided deep new insights into enzymatic transfer of halide equivalents in three oxidation states. These are (1) the halide ions (X-) abundant in nature, (2) halogen atoms (X*), and (3) the X+ equivalents. The mechanism of halogen incorporation is tailored to the electronic demands of specific substrates and involves enzymes with distinct redox coenzyme requirements.
Topics: Biological Products; Halogenation; Oxidation-Reduction; Peroxidases
PubMed: 17881282
DOI: 10.1016/j.cbpa.2007.08.002