-
Molecules (Basel, Switzerland) Feb 2020Invertebrates are an important source of structurally-diverse and biologically-active halogenated metabolites. The sea hare Rang has long been known to possess... (Review)
Review
Invertebrates are an important source of structurally-diverse and biologically-active halogenated metabolites. The sea hare Rang has long been known to possess halogenated metabolites of dietary origin that are used as a self-defense mechanism. The compounds from Rang are comprised mainly of terpenoids and small percentages of C-15 acetogenins, indoles, macrolides, sterols and alkaloids with potent cytotoxic, anti-microbial and anti-inflammatory properties. For decades the metabolites discovered have been investigated for their medical and pharmaceutical applications, so much so that the ecological role of the metabolites has been overlooked. The interaction between Rang and its diet that is comprised of seaweed can provide information into the distribution and diversity of the seaweed, the application of bioaccumulated secondary metabolites as part of its defense mechanism and the potential roles of these metabolites for adaptation in the marine environment. This paper compiles the diversity of halogenated secondary metabolites documented from Rang.
Topics: Acetogenins; Alkaloids; Animals; Aplysia; Halogenation; Indoles; Macrolides; Seaweed; Sterols
PubMed: 32070000
DOI: 10.3390/molecules25040815 -
Molecules (Basel, Switzerland) Feb 2020Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside...
Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3'- and 2'-fluorinated ProTides following different radiosynthetic approaches. The 3'-[F]FLT ProTide was obtained via a late stage [F]fluorination in radiochemical yields (RCY) of 15-30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2'-[F]FIAU ProTide was obtained via an early stage [F]fluorination approach with an RCY of 1-5% ( = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/mol (total synthesis time of 240 min).
Topics: Fluorine Radioisotopes; Halogenation; Nucleotides; Positron-Emission Tomography; Radiochemistry; Radiopharmaceuticals
PubMed: 32041321
DOI: 10.3390/molecules25030704 -
Bromine, iodine and sodium along the EAIIST traverse: Bulk and surface snow latitudinal variability.Environmental Research Dec 2023During the East Antarctic International Ice Sheet Traverse (Eaiist, december 2019), in an unexplored part of the East Antarctic Plateau, snow samples were collected to...
During the East Antarctic International Ice Sheet Traverse (Eaiist, december 2019), in an unexplored part of the East Antarctic Plateau, snow samples were collected to expand our knowledge of the latitudinal variability of iodine, bromine and sodium as well as their relation in connection with emission processes and photochemical activation in this unexplored area. A total of 32 surface (0-5 cm) and 32 bulk (average of 1 m depth) samples were taken and analysed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Our results show that there is no relevant latitudinal trend for bromine and sodium. For bromine they also show that it has no significant post-depositional mechanisms while its inland surface snow concentration is influenced by spring coastal bromine explosions. Iodine concentrations are several orders of magnitude lower than bromine and sodium and they show a decreasing trend in the surface samples concentration moving southward. This suggests that other processes affect its accumulation in surface snow, probably related to the radial reduction in the ozone layer moving towards central Antarctica. Even though all iodine, bromine and sodium present similar long-range transport from the dominant coastal Antarctic sources, the annual seasonal cycle of the ozone hole over Antarctica increases the amount of UV radiation (in the 280-320 nm range) reaching the surface, thereby affecting the surface snow photoactivation of iodine. A comparison between the bulk and surface samples supports the conclusion that iodine undergoes spring and summer snow recycling that increases its atmospheric lifetime, while it tends to accumulate during the winter months when photochemistry ceases.
Topics: Iodine; Bromine; Snow; Sodium; Antarctic Regions
PubMed: 37821067
DOI: 10.1016/j.envres.2023.117344 -
Natural Product Reports Oct 2021Covering: Up to December 2020Enzymatic halogenation reactions are essential for the production of thousands of halogenated natural products. However, in recent years,... (Review)
Review
Covering: Up to December 2020Enzymatic halogenation reactions are essential for the production of thousands of halogenated natural products. However, in recent years, scientists discovered several halogenases that transiently incorporate halogen atoms in intermediate biosynthetic molecules to activate them for further chemical reactions such as cyclopropanation, terminal alkyne formation, C-/O-alkylation, biaryl coupling, and C-C rearrangements. In each case, the halogen atom is lost in the course of biosynthesis to the final product and is hence termed "cryptic". In this review, we provide an overview of our current knowledge of cryptic halogenation reactions in natural product biosynthesis.
Topics: Biological Products; Halogenation
PubMed: 34676862
DOI: 10.1039/d1np00010a -
Molecules (Basel, Switzerland) May 2022Limonene (1-methyl-4-(1-methylethenyl)-cyclohexene) is one of the most widespread monocyclic terpenes, being both a natural and industrial compound. It is widely present...
Limonene (1-methyl-4-(1-methylethenyl)-cyclohexene) is one of the most widespread monocyclic terpenes, being both a natural and industrial compound. It is widely present in the environment, including in water supplies. Therefore, it may be subjected to aqueous chlorination at water treatment stations during drinking water preparation. Besides, being a component of numerous body care and cosmetic products, it may present at high levels in swimming pool waters and could also be subjected to aqueous chlorination. Laboratory experiments with aqueous chlorination of D-limonene demonstrated the prevalence of the conjugated electrophilic addition of HOCl molecule to the double bonds of the parent molecule as the primary reaction. The reaction obeys the Markovnikov rule, as the levels of the corresponding products were higher than those of the alternative ones. Fragmentation pattern in conditions of electron ionization enabled the assigning of the structures for four primary products. The major products of the chlorination are formed by the addition of two HOCl molecules to limonene. The reactions of electrophilic addition are usually accompanied by the reactions of elimination. Thus, the loss of water molecules from the products of various generations results in the reproduction of the double bond, which immediately reacts further. Thus, a cascade of addition-elimination reactions brings the most various isomeric polychlorinated species. At a ratio of limonene/active chlorine higher than 1:10, the final products of aqueous chlorination (haloforms) start forming, while brominated haloforms represent a notable portion of these products due to the presence of bromine impurities in the used NaOCl. It is worth mentioning that the bulk products of aqueous chlorination are less toxic in the bioluminescence test on than the parent limonene.
Topics: Chlorine; Disinfection; Halogenation; Limonene; Water Pollutants, Chemical; Water Purification
PubMed: 35566337
DOI: 10.3390/molecules27092988 -
Environmental Science and Pollution... Feb 2021Chlorine (Cl) in the terrestrial environment is of interest from multiple perspectives, including the use of chloride as a tracer for water flow and contaminant... (Review)
Review
Chlorine (Cl) in the terrestrial environment is of interest from multiple perspectives, including the use of chloride as a tracer for water flow and contaminant transport, organochlorine pollutants, Cl cycling, radioactive waste (radioecology; Cl is of large concern) and plant science (Cl as essential element for living plants). During the past decades, there has been a rapid development towards improved understanding of the terrestrial Cl cycle. There is a ubiquitous and extensive natural chlorination of organic matter in terrestrial ecosystems where naturally formed chlorinated organic compounds (Cl) in soil frequently exceed the abundance of chloride. Chloride dominates import and export from terrestrial ecosystems while soil Cl and biomass Cl can dominate the standing stock Cl. This has important implications for Cl transport, as chloride will enter the Cl pools resulting in prolonged residence times. Clearly, these pools must be considered separately in future monitoring programs addressing Cl cycling. Moreover, there are indications that (1) large amounts of Cl can accumulate in biomass, in some cases representing the main Cl pool; (2) emissions of volatile organic chlorines could be a significant export pathway of Cl and (3) that there is a production of Cl in tissues of, e.g. plants and animals and that Cl can accumulate as, e.g. chlorinated fatty acids in organisms. Yet, data focusing on ecosystem perspectives and combined spatiotemporal variability regarding various Cl pools are still scarce, and the processes and ecological roles of the extensive biological Cl cycling are still poorly understood.
Topics: Chlorides; Chlorine; Ecosystem; Halogenation; Soil
PubMed: 33400105
DOI: 10.1007/s11356-020-12144-6 -
Biomolecules Dec 2022Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality....
Halogenation of bioactive peptides via incorporation of non-natural amino acid derivatives during chemical synthesis is a common strategy to enhance functionality. Bacterial tyrptophan halogenases efficiently catalyze regiospecific halogenation of the free amino acid tryptophan, both in vitro and in vivo. Expansion of their substrate scope to peptides and proteins would facilitate highly-regulated post-synthesis/expression halogenation. Here, we demonstrate novel in vitro halogenation (chlorination and bromination) of peptides by select halogenase enzymes and identify the C-terminal (G/S)GW motif as a preferred substrate. In a first proof-of-principle experiment, we also demonstrate chemo-catalyzed derivatization of an enzymatically chlorinated peptide, albeit with low efficiency. We further rationally derive PyrH halogenase mutants showing improved halogenation of the (G/S)GW motif, both as a free peptide and when genetically fused to model proteins with efficiencies up to 90%.
Topics: Halogenation; Oxidoreductases; Bacterial Proteins; Peptides; Amino Acids
PubMed: 36551269
DOI: 10.3390/biom12121841 -
Chembiochem : a European Journal of... Jan 2023The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or...
The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or conjugation of bioactive compounds. The development of orthogonal methods for C-H functionalisation is crucial for such peptide derivatisation. Among them, biocatalytic methods are increasingly attracting attention. Tryptophan halogenases emerged as valuable catalysts to functionalise tryptophan (Trp), while direct enzyme-catalysed halogenation of synthetic peptides is yet unprecedented. Here, it is reported that the Trp 6-halogenase Thal accepts a wide range of amides and peptides containing a Trp moiety. Increasing the sequence length and reaction optimisation made bromination of pentapeptides feasible with good turnovers and a broad sequence scope, while regioselectivity turned out to be sequence dependent. Comparison of X-ray single crystal structures of Thal in complex with d-Trp and a dipeptide revealed a significantly altered binding mode for the peptide. The viability of this bioorthogonal approach was exemplified by halogenation of a cyclic RGD peptide.
Topics: Halogenation; Tryptophan; Peptides; Structure-Activity Relationship; Catalysis
PubMed: 36259362
DOI: 10.1002/cbic.202200569 -
Journal of the American Chemical Society Feb 2020Alkoxy radicals have long been known to enable remote C-H functionalization via 1,5-hydrogen atom abstraction. However, methods for their generation traditionally have...
Alkoxy radicals have long been known to enable remote C-H functionalization via 1,5-hydrogen atom abstraction. However, methods for their generation traditionally have relied upon highly oxidizing metals, ultraviolet radiation, or preformed peroxide intermediates, which has prevented the development of many desirable transformations. Herein we report a new bench-stable precursor that decomposes to free alkoxy radicals via a previously unreported single-electron oxidation pathway. This new precursor enables the fluorination and chlorination of remote C-H bonds under exceptionally mild conditions with exceedingly high monoselectivity. Iterative use of this precursor enables the introduction of a second halogen atom, granting access to remote dihalide motifs, including CF and CFCl.
Topics: Alcohols; Catalysis; Halogenation; Oxidation-Reduction; Palladium; Photochemical Processes
PubMed: 31999441
DOI: 10.1021/jacs.9b13171 -
Angewandte Chemie (International Ed. in... Aug 2022In synthetic method development, the most rewarding path is seldom a straight line. While our initial entry into pentafluorosulfanyl (SF ) chemistry did not go according... (Review)
Review
In synthetic method development, the most rewarding path is seldom a straight line. While our initial entry into pentafluorosulfanyl (SF ) chemistry did not go according to plan (due to inaccessibility of reagents such as SF Cl at the time), a "detour" led us to establish mild and inexpensive oxidative fluorination conditions that made aryl-SF compound synthesis more accessible. The method involved the use of potassium fluoride and trichloroisocyanuric acid (TCICA)-a common swimming pool disinfectant-as opposed to previously employed reagents such as F , XeF , HF, and Cl . Thereafter, curiosity led us to explore applications of TCICA/KF as a more general approach to the synthesis of fluorinated Group 15, 16, and 17 heteroatoms in organic scaffolds; this, in turn, prompted SC-XRD, VT-NMR, computational, and physical organic studies. Ultimately, it was discovered that TCICA/KF can be used to synthesize SF Cl, enabling SF chemistry in an unexpected way.
Topics: Fluorides; Halogenation; Indicators and Reagents; Oxidative Stress; Potassium Compounds; Triazines
PubMed: 35580251
DOI: 10.1002/anie.202205088