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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 -
International Journal of Molecular... Jun 2023Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with...
Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure-activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.
Topics: Humans; Bromine; Antineoplastic Agents; Anti-Inflammatory Agents; Cyclooxygenase 2; Nitric Oxide Synthase Type II; Inflammation; Benzofurans; Carcinogenesis; Nitric Oxide; Lipopolysaccharides; Tumor Microenvironment
PubMed: 37373544
DOI: 10.3390/ijms241210399 -
Andrology Jul 2020Environmental chemicals that interfere with the production and/or action of hormones may have adverse effects on male reproduction. This review focuses on the possible... (Review)
Review
BACKGROUND
Environmental chemicals that interfere with the production and/or action of hormones may have adverse effects on male reproduction. This review focuses on the possible impact of exposure to flame retardant chemicals on male reproduction. Flame retardants are added to a wide variety of combustible materials to prevent fires from starting, slow their spread, and provide time to escape. However, these chemicals are often additive so they leach out into the environment. Governments have restricted the use of polybrominated diphenyl ether flame retardants based on evidence that they are persistent and bioaccumulate and have adverse effects on health. The phasing out of these "legacy" flame retardants has resulted in their replacement with alternatives, such as tetrabromobisphenol A and the organophosphate esters.
OBJECTIVE
To review the literature on the effects of brominated and organophosphate ester flame retardant chemicals on male reproduction.
METHODS
PubMed database was searched for studies reporting the effects of brominated and organophosphate ester flame retardants on male reproduction.
RESULTS
Cell-based, animal model, and human studies provide evidence that the polybrominated diphenyl ethers act as endocrine-disrupting chemicals; further, exposure during critical windows of development may be associated with a permanent impact on male reproduction. In vitro and animal model data are accumulating with respect to the effects of tetrabromobisphenol A and organophosphate esters, but few studies have evaluated their impact on human health.
CONCLUSIONS
More research on human exposure to replacement flame retardants and the possibility that they may be associated with adverse reproductive health outcomes is a high priority.
Topics: Animals; Bromine; Endocrine Disruptors; Environmental Pollutants; Flame Retardants; Genitalia, Male; Halogenated Diphenyl Ethers; Humans; Male; Organophosphates; Polybrominated Biphenyls
PubMed: 32216051
DOI: 10.1111/andr.12789 -
Molecules (Basel, Switzerland) Jul 2020In this review, recent advances over the past decade in the preparation of fluorinated stereogenic quaternary centers on -keto esters compounds are analyzed. Since the... (Review)
Review
In this review, recent advances over the past decade in the preparation of fluorinated stereogenic quaternary centers on -keto esters compounds are analyzed. Since the incorporation of fluorine and fluorinated groups is of special interest in pharmaceutical chemistry, a range of metal-catalyzed and organocatalyzed methods have been developed. Herein, we review the enantioselective fluorination, trifluoromethylation and trifluoromethylthiolation of 3-oxo esters. The scope, the induction of enantioselectivity and mechanistic investigations are presented.
Topics: Catalysis; Esters; Fluorides; Fluorine; Halogenation; Hydrocarbons, Fluorinated; Molecular Structure; Stereoisomerism
PubMed: 32708946
DOI: 10.3390/molecules25143264 -
Molecules (Basel, Switzerland) Apr 2020This review article focused on the innovative procedure for electrophilic fluorination using HF and in situ generation of the required electrophilic species derived from... (Review)
Review
This review article focused on the innovative procedure for electrophilic fluorination using HF and in situ generation of the required electrophilic species derived from hypervalent iodine compounds. The areas of synthetic application of this approach include fluorination of 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes.
Topics: Alcohols; Catalysis; Cyclization; Fluorides; Fluorine; Halogenation; Hydrofluoric Acid; Ketones; Molecular Structure; Styrene
PubMed: 32366048
DOI: 10.3390/molecules25092116 -
Environmental Science and Pollution... Dec 2022Chlorinated disinfectants are widely used in hospitals, COVID-19 quarantine facilities, households, institutes, and public areas to combat the spread of the novel... (Review)
Review
Chlorinated disinfectants are widely used in hospitals, COVID-19 quarantine facilities, households, institutes, and public areas to combat the spread of the novel coronavirus as they are effective against viruses on various surfaces. Medical facilities have enhanced their routine disinfection of indoors, premises, and in-house sewage. Besides questioning the efficiency of these compounds in combating coronavirus, the impacts of these excessive disinfection efforts have not been discussed anywhere. The impacts of chlorine-based disinfectants on both environment and human health are reviewed in this paper. Chlorine in molecular and in compound forms is known to pose many health hazards. Hypochlorite addition to soil can increase chlorine/chloride concentration, which can be fatal to plant species if exposed. When chlorine compounds reach the sewer/drainage system and are exposed to aqueous media such as wastewater, many disinfection by-products (DBPs) can be formed depending on the concentrations of natural organic matter, inorganics, and anthropogenic pollutants present. Chlorination of hospital wastewater can also produce toxic drug-derived disinfection by-products. Many DBPs are carcinogenic to humans, and some of them are cytotoxic, genotoxic, and mutagenic. DBPs can be harmful to the flora and fauna of the receiving water body and may have adverse effects on microorganisms and plankton present in these ecosystems.
Topics: Humans; Disinfectants; Chlorine; COVID-19; Wastewater; Water Purification; Chlorides; Ecosystem; Pandemics; Water Pollutants, Chemical; Disinfection; Halogenation; Halogens
PubMed: 35091954
DOI: 10.1007/s11356-021-18316-2 -
Nature Communications Aug 2022Protein halogenation is a common non-enzymatic post-translational modification contributing to aging, oxidative stress-related diseases and cancer. Here, we report a...
Protein halogenation is a common non-enzymatic post-translational modification contributing to aging, oxidative stress-related diseases and cancer. Here, we report a genetically encodable halogenation of tyrosine residues in a reconstituted prokaryotic filamentous cell-division protein (FtsZ) as a platform to elucidate the implications of halogenation that can be extrapolated to living systems of much higher complexity. We show how single halogenations can fine-tune protein structures and dynamics of FtsZ with subtle perturbations collectively amplified by the process of FtsZ self-organization. Based on experiments and theories, we have gained valuable insights into the mechanism of halogen influence. The bending of FtsZ structures occurs by affecting surface charges and internal domain distances and is reflected in the decline of GTPase activities by reducing GTP binding energy during polymerization. Our results point to a better understanding of the physiological and pathological effects of protein halogenation and may contribute to the development of potential diagnostic tools.
Topics: Bacterial Proteins; Cytoskeletal Proteins; Guanosine Triphosphate; Halogenation; Protein Binding; Tyrosine
PubMed: 35977922
DOI: 10.1038/s41467-022-32535-2 -
Effect of bromine and iodine chemistry on tropospheric ozone over Asia-Pacific using the CMAQ model.Chemosphere Jan 2021Recent studies have focused on the chemistry of tropospheric halogen species which are able to deplete tropospheric ozone (O). In this study, the effect of bromine and...
Recent studies have focused on the chemistry of tropospheric halogen species which are able to deplete tropospheric ozone (O). In this study, the effect of bromine and iodine chemistry on tropospheric O within the annual cycle in Asia-Pacific is investigated using the CMAQ model with the newly embedded bromine and iodine chemistry and a blended and customized emission inventory considering marine halogen emission. Results indicate that the vertical profiles of bromine and iodine species show distinct features over land/ocean and daytime/nighttime, related to natural and anthropogenic emission distributions and photochemical reactions. The halogen-mediated O loss has a strong seasonal cycle, and reaches a maximum of -15.9 ppbv (-44.3%) over the ocean and -13.4 ppbv (-38.9%) over continental Asia among the four seasons. Changes in solar radiation, dominant wind direction, and nearshore chlorophyll-a accumulation all contribute to these seasonal differences. Based on the distances to the nearest coastline, the onshore and offshore features of tropospheric O loss caused by bromine and iodine chemistry are studied. Across a coastline-centric 400-km-wide belt from onshore to offshore, averaged maximum gradient of O loss reaches 1.1 ppbv/100 km at surface level, while planetary boundary layer (PBL) column mean of O loss is more moderate, being approximately 0.7 ppbv/100 km. Relative high halogen can be found over Tibetan Plateau (TP) and the largest O loss (approximately 4-5 ppbv) in the PBL can be found between the western boundary of the domain and the TP. Halogens originating from marine sources can potentially affect O concentration transported from the stratosphere over the TP region. As part of efforts to improve our understanding of the effect of bromine and iodine chemistry on tropospheric O, we call for more models and monitoring studies on halogen chemistry and be considered further in air pollution prevention and control policy.
Topics: Air Pollutants; Air Pollution; Asia; Bromine; Halogens; Iodides; Iodine; Ozone; Seasons
PubMed: 32784061
DOI: 10.1016/j.chemosphere.2020.127595 -
Molecules (Basel, Switzerland) May 2020The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a...
The incorporation of the trifluoromethoxy group into organic molecules has become very popular due to the unique properties of the named substituent that has a "pseudohalogen" character, while the chemical properties of the synthesized compound, especially heterocycles with such a group, are less studied. As trifluoromethoxy-substituted pyrazines are still unknown, we have developed efficient and scalable methods for 2-chloro-5-trifluoromethoxypyrazine synthesis, showing the synthetic utility of this molecule for Buchwald-Hartwig amination and the Kumada-Corriu and Suzuki and Sonogashira coupling reactions. Some comparisons of chlorine atom and trifluoromethoxy group stability in these transformations have been carried out.
Topics: Amination; Halogenation; Molecular Structure; Proton Magnetic Resonance Spectroscopy; Pyrazines
PubMed: 32397388
DOI: 10.3390/molecules25092226 -
Journal of the American Chemical Society Aug 2023The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic...
The biosynthetic installation of halogen atoms is largely performed by oxidative halogenases that target a wide array of electron-rich substrates, including aromatic compounds and conjugated systems. Halogenated alkyne-containing molecules are known to occur in Nature; however, halogen atom installation on the terminus of an alkyne has not been demonstrated in enzyme catalysis. Herein, we report the discovery and characterization of an alkynyl halogenase in natural product biosynthesis. We show that the flavin-dependent halogenase from the jamaicamide biosynthetic pathway, JamD, is not only capable of terminal alkyne halogenation on a late-stage intermediate en route to the final natural product but also has broad substrate tolerance for simple to complex alkynes. Furthermore, JamD is specific for terminal alkynes over other electron-rich aromatic substrates and belongs to a newly identified family of halogenases from marine cyanobacteria, indicating its potential as a chemoselective biocatalyst for the formation of haloalkynes.
Topics: Halogenation; Halogens; Alkynes; Biological Products; Catalysis
PubMed: 37594919
DOI: 10.1021/jacs.3c05750