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Nuclear Medicine and Biology 2021Hydrogen cyanide (HCN) is a versatile synthon for generating carbon‑carbon and carbon-heteroatom bonds. Unlike other one-carbon synthons (i.e., CO, CO), HCN can... (Review)
Review
Hydrogen cyanide (HCN) is a versatile synthon for generating carbon‑carbon and carbon-heteroatom bonds. Unlike other one-carbon synthons (i.e., CO, CO), HCN can function as a nucleophile (as in potassium cyanide, KCN) and an electrophile (as in cyanogen bromide, (CN)Br). The incorporation of the CN motif into organic molecules generates nitriles, hydantoins and (thio)cyanates, which can be converted to carboxylic acids, aldehydes, amides and amines. Such versatile chemistry is particularly attractive in PET radiochemistry where diverse bioactive small molecules incorporating carbon-11 in different positions need to be produced. The first examples of making [C]HCN for radiolabeling date back to the 1960s. During the ensuing decades, [C]cyanide labeling was popular for producing biologically important molecules including C-labeled α-amino acids, sugars and neurotransmitters. [C]cyanation is now reemerging in many PET centers due to its versatility for making novel tracers. Here, we summarize the chemistry of [C]HCN, review the methods to make [C]HCN past and present, describe methods for labeling different types of molecules with [C]HCN, and provide an overview of the reactions available to convert nitriles into other functional groups. Finally, we discuss some of the challenges and opportunities in [C]HCN labeling such as developing more robust methods to produce [C]HCN and developing rapid and selective methods to convert nitriles into other functional groups in complex molecules.
Topics: Positron-Emission Tomography
PubMed: 34624831
DOI: 10.1016/j.nucmedbio.2021.09.002 -
Current Research in Microbial Sciences 2022Modern intensive agricultural practices face numerous challenges that pose major threats to global food security. In order to address the nutritional requirements of the... (Review)
Review
Modern intensive agricultural practices face numerous challenges that pose major threats to global food security. In order to address the nutritional requirements of the ever-increasing world population, chemical fertilizers and pesticides are applied on large scale to increase crop production. However, the injudicious use of agrochemicals has resulted in environmental pollution leading to public health hazards. Moreover, agriculture soils are continuously losing their quality and physical properties as well as their chemical (imbalance of nutrients) and biological health. Plant-associated microbes with their plant growth- promoting traits have enormous potential to solve these challenges and play a crucial role in enhancing plant biomass and crop yield. The beneficial mechanisms of plant growth improvement include enhanced nutrient availability, phytohormone modulation, biocontrol of phytopathogens and amelioration of biotic and abiotic stresses. Solid-based or liquid bioinoculant formulation comprises inoculum preparation, addition of cell protectants such as glycerol, lactose, starch, a good carrier material, proper packaging and best delivery methods. Recent developments of formulation include entrapment/microencapsulation, nano-immobilization of microbial bioinoculants and biofilm-based biofertilizers. This review critically examines the current state-of-art on use of microbial strains as biofertilizers and the important roles performed by these beneficial microbes in maintaining soil fertility and enhancing crop productivity.
PubMed: 35024641
DOI: 10.1016/j.crmicr.2021.100094 -
BMJ Case Reports Jul 2019While potassium cyanide poisoning has been well described, the toxicity of potassium gold cyanide is less well understood. This case describes an 84-year-old man who...
While potassium cyanide poisoning has been well described, the toxicity of potassium gold cyanide is less well understood. This case describes an 84-year-old man who presented after an intentional ingestion of 0.5-1 teaspoons of potassium gold cyanide. Despite antidotal therapy, the patient rapidly developed severe lactic acidosis, multiorgan dysfunction and ultimately expired. While the patient's clinical findings were consistent with acute cyanide poisoning, a serum cyanide level was below the toxic threshold. Previous reports have suggested that gold toxicity may also contribute to the effects of potassium gold cyanide, and may have played a role in the patient's rapid decline. In addition to treatment of cyanide toxicity, management of acute gold toxicity should also be considered in potassium gold cyanide ingestion.
Topics: Acidosis, Lactic; Aged, 80 and over; Cyanates; Gold; Gold Compounds; Humans; Male; Potassium Cyanide; Suicide
PubMed: 31350229
DOI: 10.1136/bcr-2019-229947 -
Toxicological Sciences : An Official... Jan 2023Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational...
Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.
Topics: Swine; Animals; Cyanides; Disease Models, Animal; Antidotes; Hemodynamics; Glyoxylates; Poisoning
PubMed: 36326479
DOI: 10.1093/toxsci/kfac116 -
MBio Apr 2022The bacterial response to antibiotics eliciting resistance is one of the key challenges in global health. Despite many attempts to understand intrinsic antibiotic...
The bacterial response to antibiotics eliciting resistance is one of the key challenges in global health. Despite many attempts to understand intrinsic antibiotic resistance, many of the underlying mechanisms still remain elusive. In this study, we found that iron supplementation promoted antibiotic resistance in Streptomyces coelicolor. Iron-promoted resistance occurred specifically against bactericidal antibiotics, irrespective of the primary target of antibiotics. Transcriptome profiling revealed that some genes in the central metabolism and respiration were upregulated under iron-replete conditions. Iron supported the growth of S. coelicolor even under anaerobic conditions. In the presence of potassium cyanide, which reduces aerobic respiration of cells, iron still promoted respiration and antibiotic resistance. This suggests the involvement of a KCN-insensitive type of respiration in the iron effect. This phenomenon was also observed in another actinobacterium, Mycobacterium smegmatis. Taken together, these findings provide insight into a bacterial resistance strategy that mitigates the activity of bactericidal antibiotics whose efficacy accompanies oxidative damage by switching the respiration mode. A widely investigated mode of antibiotic resistance occurs via mutations and/or by horizontal acquisition of resistance genes. In addition to this acquired resistance, most bacteria exhibit intrinsic resistance as an inducible and adaptive response to different classes of antibiotics. Increasing attention has been paid recently to intrinsic resistance mechanisms because this may provide novel therapeutic targets that help rejuvenate the efficacy of the current antibiotic regimen. In this study, we demonstrate that iron promotes the intrinsic resistance of aerobic actinomycetes Streptomyces coelicolor and Mycobacterium smegmatis against bactericidal antibiotics. A surprising role of iron to increase respiration, especially in a mode of using less oxygen, appears a fitting strategy to cope with bactericidal antibiotics known to kill bacteria through oxidative damage. This provides new insights into developing antimicrobial treatments based on the availability of iron and oxygen.
Topics: Actinobacteria; Anti-Bacterial Agents; Bacteria; Drug Resistance, Microbial; Iron; Oxygen; Respiration; Streptomyces coelicolor
PubMed: 35357210
DOI: 10.1128/mbio.00425-22 -
Applied and Environmental Microbiology Oct 2023grows as a biofilm under many environmental conditions, and the bacterium can disperse from biofilms via highly regulated, dynamic processes. However, physiologic...
grows as a biofilm under many environmental conditions, and the bacterium can disperse from biofilms via highly regulated, dynamic processes. However, physiologic triggers of biofilm dispersal remain poorly understood. Based on prior literature describing dispersal triggered by forms of starvation, we tested bacterial respiratory inhibitors for biofilm dispersal in two models resembling chronic airway infections. Our underlying hypothesis was that respiratory inhibitors could serve as a model for the downstream effects of starvation. We used two experimental conditions. In the first condition, biofilms were grown and dispersed from the surface of airway epithelial cells, and the second condition was a model where biofilms were grown on glass in cell culture media supplemented with host-relevant iron sources. In both biofilm models, the respiratory inhibitors potassium cyanide and sodium azide each triggered biofilm dispersal. We hypothesized that cyanide-induced dispersal was due to respiratory inhibition rather than signaling via an alternative mechanism, and, indeed, if respiration was supported by overexpression of cyanide-insensitive oxidase, dispersal was prevented. Dispersal required the activity of the cyclic-di-GMP regulated protease LapG, reinforcing the role of matrix degradation in dispersal. Finally, we examined the roles of individual phosphodiesterases, previously implicated in dispersal to specific triggers, and found signaling to be highly redundant. Combined deletion of the phosphodiesterases , , and was required to attenuate the dispersal phenotype. In summary, this work adds insight into the physiology of biofilm dispersal under environmental conditions in which bacterial respiration is abruptly limited. IMPORTANCE The bacterium grows in biofilm communities that are very difficult to treat in human infections. Growing as a biofilm can protect bacteria from antibiotics and the immune system. Bacteria can leave a biofilm through a process called "dispersal." Dispersed bacteria seed new growth areas and are more susceptible to killing by antibiotics. The triggers for biofilm dispersal are not well understood, and if we understood dispersal better it might lead to the development of new treatments for infection. In this paper, we find that inhibiting ability to respire (generate energy) can trigger dispersal from a biofilm grown in association with human respiratory epithelial cells in culture. The dispersal process requires a protease which is previously known to degrade the biofilm matrix. These findings give us a better understanding of how the biofilm dispersal process works so that future research can discover better ways of clearing bacteria growing in biofilms.
Topics: Humans; Pseudomonas aeruginosa; Biofilms; Phosphoric Diester Hydrolases; Anti-Bacterial Agents; Peptide Hydrolases; Cyanides; Gene Expression Regulation, Bacterial; Bacterial Proteins; Cyclic GMP
PubMed: 37728340
DOI: 10.1128/aem.01101-23 -
Journal of Labelled Compounds &... Apr 2020[ H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp CH bond ortho to the methyl ester...
[ H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [ H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [ C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [ C]cyanide.
Topics: Carbon Radioisotopes; Catalysis; Chemistry Techniques, Synthetic; Iridium; Iridoids; Isotope Labeling; Radiochemistry; Tritium
PubMed: 32017204
DOI: 10.1002/jlcr.3832 -
Organic Letters Sep 2021A nickel-catalyzed cyanation of aryl thioethers using Zn(CN) as a cyanide source has been developed to access functionalized aryl nitriles. The ligand dcype...
A nickel-catalyzed cyanation of aryl thioethers using Zn(CN) as a cyanide source has been developed to access functionalized aryl nitriles. The ligand dcype (1,2-bis(dicyclohexylphosphino)ethane) in combination with the base KOAc (potassium acetate) is essential for achieving this transformation efficiently. This reaction involves both a C-S bond activation and a C-C bond formation. The scalability, low catalyst and reagents loadings, and high functional group tolerance have enabled both late-stage derivatization and polymer recycling, demonstrating the reaction's utility across organic chemistry.
PubMed: 34433260
DOI: 10.1021/acs.orglett.1c02285 -
Clinical Toxicology (Philadelphia, Pa.) Mar 2020Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although...
Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment. We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured. Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics. In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.
Topics: Animals; Antidotes; Chelating Agents; Cyanides; Disease Models, Animal; Dose-Response Relationship, Drug; Edetic Acid; Hydroxocobalamin; Male; Pre-Exposure Prophylaxis; Swine; Swine, Miniature
PubMed: 31389254
DOI: 10.1080/15563650.2019.1628969