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Journal of Medicinal Chemistry Apr 2024Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to...
Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH···O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.
PubMed: 38670538
DOI: 10.1021/acs.jmedchem.3c02286 -
Toxics Apr 2024Organophosphate esters (OPEs) are frequently used as flame retardants and plasticizers in various commercial products. While initially considered as substitutes for...
Organophosphate esters (OPEs) are frequently used as flame retardants and plasticizers in various commercial products. While initially considered as substitutes for brominated flame retardants, they have faced restrictions in some countries due to their toxic effects on organisms. We collected 37 soil and crop samples in 20 cities along the coast of South China, and OPEs were detected in all of them. Meanwhile, we studied the contamination and potential human health risks of OPEs. In soil samples, the combined concentrations of eight OPEs varied between 74.7 and 410 ng/g, averaging at 255 ng/g. Meanwhile, in plant samples, the collective concentrations of eight OPEs ranged from 202 to 751 ng/g, with an average concentration of 381 ng/g. TDCIPP, TCPP, TCEP, and ToCP were the main OPE compounds in both plant and soil samples. Within the study area, the contaminants showed different spatial distributions. Notably, higher OPEs were found in coastal agricultural soils in Guangdong Province and crops in the Guangxi Zhuang Autonomous Region. The results of an ecological risk assessment show that the farmland soil along the southern coast of China is at high or medium ecological risk. The average non-carcinogenic risk and the carcinogenic risk of OPEs in soil through ingestion and dermal exposure routes are within acceptable levels. Meanwhile, this study found that the dietary intake of OPEs through food is relatively low, but twice as high as other studies, requiring serious attention. The research findings suggest that the human risk assessment indicates potential adverse effects on human health due to OPEs in the soil-plant system along the coast of South China. This study provides a crucial foundation for managing safety risks in agricultural operations involving OPEs.
PubMed: 38668509
DOI: 10.3390/toxics12040286 -
Toxics Apr 2024Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and...
Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study.
Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRβ. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32-25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR-ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6'-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRβ, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRβ was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3',5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6'-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.
PubMed: 38668504
DOI: 10.3390/toxics12040281 -
Chemical Science Apr 2024The halocyclization reaction represents one of the most common methodologies for the synthesis of heterocyclic molecules. Many efforts have been made to balance the...
The halocyclization reaction represents one of the most common methodologies for the synthesis of heterocyclic molecules. Many efforts have been made to balance the relationship between structure, reactivity and selectivity, including the design of new electrophilic halogenation reagents and the utilization of activating strategies. However, discovering universal reagents or activating strategies for electrophilic halocyclization remains challenging due to the case-by-case practice for different substrates or different cyclization models. Here we report an intramolecular chaperone-assisted dual-anchoring activation (ICDA) model for electrophilic halocyclization, taking advantage of the non-covalent dual-anchoring orientation as the driving force. This protocol allows a practical, catalyst-free and rapid approach to access seven types of small-sized, medium-sized, and large-sized heterocyclic units and to realize polyene-like domino halocyclizations, as exemplified by nearly 90 examples, including a risk-reducing flow protocol for gram-scale synthesis. DFT studies verify the crucial role of ICDA in affording a suitable preorganization for transition state stabilization and X transfer acceleration. The utilization of the ICDA model allows a spatiotemporal adjustment to straightforwardly obtain fast, selective and high-yielding synthetic transformations.
PubMed: 38665529
DOI: 10.1039/d4sc00581c -
Free Radical Biology & Medicine Aug 2024At inflammatory sites, immune cells generate oxidants including H₂O₂. Myeloperoxidase (MPO), released by activated leukocytes employs H₂O₂ and...
At inflammatory sites, immune cells generate oxidants including H₂O₂. Myeloperoxidase (MPO), released by activated leukocytes employs H₂O₂ and halide/pseudohalides to form hypohalous acids that mediate pathogen killing. Hypochlorous acid (HOCl) is a major species formed. Excessive or misplaced HOCl formation damages host tissues with this linked to multiple inflammatory diseases. Previously (Redox Biology, 2020, 28, 101331) we reported that iodide (I⁻) modulates MPO-mediated protein damage by decreasing HOCl generation with concomitant hypoiodous acid (HOI) formation. HOI may however impact on protein structure, so in this study we examined whether and how HOI, from peroxidase/H₂O₂/I⁻ systems ± Cl⁻, modifies proteins. Experiments employed MPO and lactoperoxidase (LPO) and multiple proteins (serum albumins, anastellin), with both chemical (intact protein and peptide mass mapping, LC-MS) and structural (SDS-PAGE) changes assessed. LC-MS analyses revealed dose-dependent iodination of anastellin and albumins by LPO/HO with increasing I⁻. Incubation of BSA with MPO/HO/Cl⁻ revealed modest chlorination (Tyr286, Tyr475, ∼4 %) and Met modification. Lower levels of these species, and extensive iodination at specific Tyr and His residues (>20 % modification with ≥10 μM I⁻) were detected with increasing I⁻. Anastellin dimerization was inhibited by increasing I⁻, but less marked changes were observed with albumins. These data confirm that I⁻ competes with Cl⁻ for MPO and is an efficient HOCl scavenger. These processes decrease protein chlorination and oxidation, but result in extensive iodination. This is consistent with published data on the presence of iodinated Tyr on neutrophil proteins. The biological implications of protein iodination relative to chlorination require further clarification.
Topics: Peroxidase; Halogenation; Iodides; Humans; Lactoperoxidase; Hypochlorous Acid; Hydrogen Peroxide; Oxidation-Reduction; Iodine Compounds
PubMed: 38663830
DOI: 10.1016/j.freeradbiomed.2024.04.230 -
RSC Advances Apr 2024An efficient and mild approach has been developed for the regio-selective direct C3 halogenation of pyrazolo[1,5-]pyrimidines employing readily available potassium...
An efficient and mild approach has been developed for the regio-selective direct C3 halogenation of pyrazolo[1,5-]pyrimidines employing readily available potassium halide salts and a hypervalent iodine(iii) reagent at ambient temperature. The protocol is both practical and environmentally friendly, utilizing water as a green solvent, potassium halides as an inexpensive and bench stable halogen source and PIDA as a non-toxic reagent, enabling clean and efficient halogenation at room temperature. The procedure yields a range of C3 halogenated pyrazolo[1,5-]pyrimidines in good to excellent yields. Mechanistic studies suggest the involvement of electrophilic substitution mechanism in the halogenation process.
PubMed: 38655480
DOI: 10.1039/d4ra02090a -
Scientific Reports Apr 2024Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has...
Fluorinated graphene, a two-dimensional nanomaterial composed of three atomic layers, a central carbon layer sandwiched between two layers of fluorine atoms, has attracted considerable attention across various fields, particularly for its potential use in biomedical applications. Nonetheless, scant effort has been devoted to assessing the potential toxicological implications of this nanomaterial. In this study, we scrutinize the potential impact of fluorinated graphene on a protein model, HP35 by utilizing extensive molecular dynamics (MD) simulation methods. Our MD results elucidate that upon adsorption to the nanomaterial, HP35 undergoes a denaturation process initiated by the unraveling of the second helix of the protein and the loss of the proteins hydrophobic core. In detail, substantial alterations in various structural features of HP35 ensue, including alterations in hydrogen bonding, Q value, and RMSD. Subsequent analyses underscore that hydrophobic and van der Waals interactions (predominant), alongside electrostatic energy (subordinate), exert influence over the adsorption of HP35 on the fluorinated graphene surface. Mechanistic scrutiny attests that the unrestrained lateral mobility of HP35 on the fluorinated graphene nanomaterial primarily causes the exposure of HP35's hydrophobic core, resulting in the eventual structural denaturation of HP35. A trend in the features of 2D nanostructures is proposed that may facilitate the denaturation process. Our findings not only substantiate the potential toxicity of fluorinated graphene but also unveil the underlying molecular mechanism, which thereby holds significance for the prospective utilization of such nanomaterials in the field of biomedicine.
Topics: Graphite; Molecular Dynamics Simulation; Protein Conformation, alpha-Helical; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Protein Unfolding; Halogenation; Adsorption; Nanostructures; Peptide Fragments; Neurofilament Proteins
PubMed: 38649777
DOI: 10.1038/s41598-024-59780-3 -
IScience May 2024Light olefins are key intermediates in the synthesis of petrochemicals, and the conversion of stabilized carbon dioxide to light olefins using catalysts containing...
Light olefins are key intermediates in the synthesis of petrochemicals, and the conversion of stabilized carbon dioxide to light olefins using catalysts containing halogenated elements such as chlorine is a major challenge. Building on previous reports emphasizing the toxic effects of halogen elements on catalysts, we present the synthesis of FeMnKBr/Y catalysts. This involved the synthesis of the catalyst by melt permeation using Br-containing potassium salts, other metal nitrates and Y zeolites. The catalyst performed well in converting syngas (H/CO = 3) to light olefins with a selectivity of 56.2%, CO conversion of 34.4%, and CO selectivity of 13.6%. Adding Br aids in reducing the Fe phase, boosts catalyst carburization, and produces more iron carbide species. It also moderately deposits carbon on the active center's surface, enhancing active phase dispersion. Br's electronegativity mitigates the influence of K, reducing catalyst's carbon-carbon coupling ability, leading to more low-carbon olefins generation.
PubMed: 38638568
DOI: 10.1016/j.isci.2024.109621 -
MethodsX Jun 2024Dust is a sink for many semi-volatile compounds including flame retardants of the organophosphate ester (OPE) and brominated flame-retardant (BFR) classes. Given the...
Dust is a sink for many semi-volatile compounds including flame retardants of the organophosphate ester (OPE) and brominated flame-retardant (BFR) classes. Given the large amount of time that we spend indoors, our exposure to these compounds via dust is of significant interest. Here, we present a novel microextraction approach to determine quantitative levels of selected OPEs and BFRs sampled from residential air filters from HVAC systems using a small volume of solvent. Dust samples (25 mg) is extracted with 1 mL of hexane/acetone (50/50, v/v). Upon solvent extraction of these HVAC dust samples, the analytes (TCPP, TDCPP, TPHP, T24DtBPP, TBBPA, and TriBBPA) were quantified via gas chromatography-mass spectrometry (GC/MS) or liquid chromatography-mass spectrometry (LC/MS). The methods for extracting these compounds from HVAC dust samples are detailed here with extensive method validation data to demonstrate accuracy and precision of these methods. •Dust is a sink for many semi-volatile compounds, including novel or emerging indoor pollutants like the organophosphate ester flame retardant T24DtBPP.•Here, a small amount of dust (25 mg) is extracted with a small volume of solvent (1 mL hexane and acetone) prior to analysis via chromatographic separation and mass spectrometric detection.
PubMed: 38633417
DOI: 10.1016/j.mex.2024.102693 -
ACS ES&T Water Apr 2024Augmenting seawater with wastewater has the potential to reduce the energy demand and environmental impacts associated with seawater desalination. Alternatively, as...
Augmenting seawater with wastewater has the potential to reduce the energy demand and environmental impacts associated with seawater desalination. Alternatively, as wastewater reuse becomes more widespread, augmenting wastewater with seawater can increase the available water supply. However, the chemistry of disinfecting a blended stream has not been explored. Toxic byproducts, including -nitrosodimethylamine (NDMA), are expected to form during disinfection, and the extent of formation will likely be a function of which stream is chlorinated and whether disinfection happens before or after blending. In this work, three blending-disinfection scenarios were modeled and experimentally evaluated in bench-scale systems treating synthetic and authentic waters. Modeling results suggested that chlorinating preblended wastewater and seawater would produce the most NDMA because it yielded the highest concentrations of bromochloramine, which was previously found to promote NDMA formation. However, chlorinating wastewater prior to blending with seawater, which modeling indicated would form the most dichloramine, produced the most NDMA in experiments. When seawater was disinfected prior to blending with wastewater, bromide likely converted most chlorine to free bromine. Bromamines formed after blending, however, did not lead to an elevated level of NDMA formation. Therefore, to minimize NDMA formation when disinfecting blended wastewater-seawater, seawater should be disinfected prior to introducing wastewater.
PubMed: 38633366
DOI: 10.1021/acsestwater.3c00617