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International Journal of Environmental... Oct 2022The aromatic amino compound 5-amino-2-(trifluoromethyl)pyridine acts as an intermediate in the synthesis of pharmaceutical products. However, the toxicity profile of...
The aromatic amino compound 5-amino-2-(trifluoromethyl)pyridine acts as an intermediate in the synthesis of pharmaceutical products. However, the toxicity profile of this compound is sparse and no related poisoning events have been reported. Here, we report the case of a 35-year-old man who inhaled 5-amino-2-(trifluoromethyl)pyridine at work. After inhalation, the patient rapidly developed symptoms such as dizziness, fatigue, nausea, vomiting, chest tightness, and loss of consciousness. After admission, methemoglobinemia, hemolytic anemia, acute renal failure, and toxic encephalopathy occurred. Symptoms improved significantly after intravenous treatment with a low dose of methylene blue. This revealed that 5-amino-2-(trifluoromethyl)pyridine is toxic to the human body and can be absorbed through the respiratory tract, resulting in methemoglobinemia and toxic encephalopathy; thus, caution should be taken in industrial production.
Topics: Male; Humans; Adult; Methemoglobinemia; Methylene Blue; Anemia, Hemolytic; Pyridines; Neurotoxicity Syndromes; Poisoning
PubMed: 36360910
DOI: 10.3390/ijerph192114031 -
Accounts of Chemical Research Oct 2021Redox reactions that take place in enzymes and on the surfaces of heterogeneous catalysts often require active sites that contain multiple metals. By contrast, there are... (Review)
Review
Redox reactions that take place in enzymes and on the surfaces of heterogeneous catalysts often require active sites that contain multiple metals. By contrast, there are very few homogeneous catalysts with multinuclear active sites, and the field of organometallic chemistry continues to be dominated by the study of single metal systems. Multinuclear catalysts have the potential to display unique properties owing to their ability to cooperatively engage substrates. Furthermore, direct metal-to-metal covalent bonding can give rise to new electronic configurations that dramatically impact substrate binding and reactivity. In order to effectively capitalize on these features, it is necessary to consider strategies to avoid the dissociation of fragile metal-metal bonds in the course of a catalytic cycle. This Account describes one approach to accomplishing this goal using binucleating redox-active ligands.In 2006, Chirik showed that pyridine-diimines (PDI) have sufficiently low-lying π* levels that they can be redox-noninnocent in low-valent iron complexes. Extending this concept, we investigated a series of dinickel complexes supported by naphthyridine-diimine (NDI) ligands. These complexes can promote a broad range of two-electron redox processes in which the NDI ligand manages electron equivalents while the metals remain in a Ni(I)-Ni(I) state.Using (NDI)Ni catalysts, we have uncovered cases where having two metals in the active site addresses a problem in catalysis that had not been adequately solved using single-metal systems. For example, mononickel complexes are capable of stoichiometrically dimerizing aryl azides to form azoarenes but do not turn over due to strong product inhibition. By contrast, dinickel complexes are effective catalysts for this reaction and avoid this thermodynamic sink by binding to azoarenes in their higher-energy cis form.Dinickel complexes can also activate strong bonds through the cooperative action of both metals. Norbornadiene has a ring-strain energy that is similar to that of cyclopropane but is not prone to undergoing C-C oxidative addition with monometallic complexes. Using an (NDI)Ni complex, norbornadiene undergoes rapid ring opening by the oxidative addition of the vinyl and bridgehead carbons. An inspection of the resulting metallacycle reveals that it is stabilized through a network of secondary Ni-π interactions. This reactivity enabled the development of a catalytic carbonylative rearrangement to form fused bicyclic dienones.These vignettes and others described in this Account highlight some of the implications of metal-metal bonding in promoting a challenging step in a catalytic cycle or adjusting the thermodynamic landscape of key intermediates. Given that our studies have focused nearly exclusively on the (NDI)Ni system, we anticipate that many more such cases are left to be discovered as other transition-metal combinations and ligand classes are explored.
Topics: Coordination Complexes; Imines; Ligands; Molecular Structure; Nickel; Oxidation-Reduction; Pyridines
PubMed: 34565142
DOI: 10.1021/acs.accounts.1c00424 -
Accounts of Chemical Research Apr 2014Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I)... (Review)
Review
Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I) complexes, such as Crabtree's hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir(III) complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d(6) Ir(III) centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C^C-chelating ligands can even stabilize Ir(IV) and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar Ir(I) complexes because of their structural and electronic similarity to Pt(II) anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich Ir(III) anticancer complexes. These complexes with the formula [(Cp(x))Ir(L^L')Z](0/n+) (with Cp* or extended Cp* and L^L' = chelated C^N or N^N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form Ir(III)-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert Ir(III) complexes as potent kinase inhibitors. Octahedral cyclometalated Ir(III) complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action.
Topics: Antineoplastic Agents; Catalysis; Humans; Iridium; Ligands; NAD; Organometallic Compounds; Pyridines; Structure-Activity Relationship
PubMed: 24555658
DOI: 10.1021/ar400266c -
Nature Apr 2016In the classic Diels-Alder [4 + 2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of...
In the classic Diels-Alder [4 + 2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4π (diene) and 2π (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels-Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced by, for example, four in the tetradehydro-Diels-Alder (TDDA) and by six in the hexadehydro-Diels-Alder (HDDA) reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4π + 2π cycloaddition reaction that generates a different, highly reactive intermediate known as an α,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, α,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels-Alder (PDDA) reaction-a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC≡N), although non-participants in aza-HDDA reactions, readily function as the 2π component in PDDA cyclizations to produce, via trapping of the α,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.
Topics: Benzene; Cyclization; Cycloaddition Reaction; Diynes; Hydrogen; Hydrogenation; Isomerism; Nitriles; Oxidation-Reduction; Pyridines; Terminology as Topic; Toluene
PubMed: 27088605
DOI: 10.1038/nature17429 -
Chemphyschem : a European Journal of... Aug 2011Fluorescent nucleoside analogs, commonly used to explore nucleic acid dynamics, recognition and damage, frequently respond to a single environmental parameter. Herein we...
Fluorescent nucleoside analogs, commonly used to explore nucleic acid dynamics, recognition and damage, frequently respond to a single environmental parameter. Herein we address the development of chromophores that can simultaneously probe more than one environmental factor while having each associated with a unique spectroscopic signature. We demonstrate that an isomorphic emissive pyridine-modified 2-deoxy-uridine 1, containing multiple sensory elements, responds to changes in acidity, viscosity, and polarity. Protonation of the pyridine moiety (pK(a) 4.4) leads to enhanced emission (λ(em) =388 nm) and red-shifted absorption spectra (λ(abs) =319 nm), suggesting the formation of an intramolecular hydrogen bond with the neighboring pyrimidine carbonyl. This "locked" conformation can also be mimicked by increasing solvent viscosity, resulting in a stark enhancement of emission quantum yield. Finally, increasing solvent polarity substantially impacts the chromophore's Stokes shift [from 5.8×10(3) cm(-1) at E(T) (30)=36.4 kcal mol(-1) to 9.3 ×10(3) cm(-1) at E(T) (30)=63.1 kcal mol(-1)]. The opposite effect is seen for the impact of solvent polarity of the protonated form. The characteristic photophysical signature induced by each parameter facilitates the exploration of these environmental factors both individually and simultaneously.
Topics: Absorption; Chemistry Techniques, Analytical; DNA; Deoxyuridine; Fluorescent Dyes; Hydrogen Bonding; Hydrogen-Ion Concentration; Models, Molecular; Protons; Pyridines; Spectrometry, Fluorescence; Viscosity
PubMed: 21698743
DOI: 10.1002/cphc.201100315 -
Molecules (Basel, Switzerland) Jun 2021New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from...
New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine- functionalized derivatives. The derived pyrazolpyridine--glycosides were synthesized via heterocyclization of the -thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative and the tricyclic pyrido[3',2':4,5]furo[3,2-d]pyrimidine were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone , 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1-pyrazolo[3,4-b]pyridin-3-amine (), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate () are among the most active inhibitors with IC values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC ranges of 31.3-49.0, 19.3-55.5, 22.7-44.8, and 36.8-70.7 μM, respectively compared to doxorubicin (IC 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Doxorubicin; Drug Design; Drug Screening Assays, Antitumor; Humans; Imidazoles; Inhibitory Concentration 50; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Quantitative Structure-Activity Relationship
PubMed: 34206976
DOI: 10.3390/molecules26133923 -
Molecules (Basel, Switzerland) Apr 2024Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted... (Review)
Review
Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine-imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.
Topics: Copper; Dendrimers; Humans; Pyridines; Antineoplastic Agents; Coordination Complexes; Schiff Bases; Imines; Neoplasms; Animals; Chelating Agents
PubMed: 38675623
DOI: 10.3390/molecules29081800 -
Journal of the American Chemical Society Nov 2019The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high...
The catalytic, enantioselective -oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine -oxides further document the utility of this approach. Demonstration of the asymmetric -oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
Topics: Aspartic Acid; Catalysis; Heterocyclic Compounds; Hydrogen Bonding; Peptides; Pyridines; Stereoisomerism
PubMed: 31656070
DOI: 10.1021/jacs.9b10414 -
Molecules (Basel, Switzerland) Aug 2021Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown... (Review)
Review
Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure-activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.
Topics: Azo Compounds; Imaging, Three-Dimensional; Phenols; Pyridines
PubMed: 34443460
DOI: 10.3390/molecules26164872 -
Tuberculosis (Edinburgh, Scotland) Jul 2021Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well...
Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated analysis of the structure-activity relationship of INH that we hope will serve as useful resource for the community.
Topics: Antitubercular Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Isoniazid; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyridines; Structure-Activity Relationship
PubMed: 34116482
DOI: 10.1016/j.tube.2021.102100