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Accounts of Chemical Research May 2018Chemical tools are transforming our understanding of biomolecules and living systems. Included in this group are bioorthogonal reagents-functional groups that are inert...
Chemical tools are transforming our understanding of biomolecules and living systems. Included in this group are bioorthogonal reagents-functional groups that are inert to most biological species, but can be selectively ligated with complementary probes, even in live cells and whole organisms. Applications of these tools have revealed fundamental new insights into biomolecule structure and function-information often beyond the reach of genetic approaches. In many cases, the knowledge gained from bioorthogonal probes has enabled new questions to be asked and innovative research to be pursued. Thus, the continued development and application of these tools promises to both refine our view of biological systems and facilitate new discoveries. Despite decades of achievements in bioorthogonal chemistry, limitations remain. Several reagents are too large or insufficiently stable for use in cellular environments. Many bioorthogonal groups also cross-react with one another, restricting them to singular tasks. In this Account, we describe our work to address some of the voids in the bioorthogonal toolbox. Our efforts to date have focused on small reagents with a high degree of tunability: cyclopropenes, triazines, and cyclopropenones. These motifs react selectively with complementary reagents, and their unique features are enabling new pursuits in biology. The Account is organized by common themes that emerged in our development of novel bioorthogonal reagents and reactions. First, natural product structures can serve as valuable starting points for probe design. Cyclopropene, triazine, and cyclopropenone motifs are all found in natural products, suggesting that they would be metabolically stable and compatible with a variety of living systems. Second, fine-tuning bioorthogonal reagents is essential for their successful translation to biological systems. Different applications demand different types of probes; thus, generating a collection of tools that span a continuum of reactivities and stabilities remains an important goal. We have used both computational analyses and mechanistic studies to guide the optimization of various cyclopropene and triazine probes. Along the way, we identified reagents that are chemoselective but best suited for in vitro work. Others are selective and robust enough for use in living organisms. The last section of this Account highlights the need for the continued pursuit of new reagents and reactions. Challenges exist when bioorthogonal chemistries must be used in concert, given that many exploit similar mechanisms and cannot be used simultaneously. Such limitations have precluded certain multicomponent labeling studies and other biological applications. We have relied on mechanistic and computational insights to identify mutually orthogonal sets of reactions, in addition to exploring unique genres of reactivity. The continued development of mechanistically distinct, biocompatible reactions will further diversify the bioorthogonal reaction portfolio for examining biomolecules.
Topics: Chemistry Techniques, Synthetic; Cycloaddition Reaction; Cyclopropanes; Indicators and Reagents; Triazines
PubMed: 29727171
DOI: 10.1021/acs.accounts.7b00606 -
Scientific Reports Feb 2022The capture and safe storage of radioactive iodine (I or I) are of a compelling significance in the generation of nuclear energy and waste storage. Because of their...
The capture and safe storage of radioactive iodine (I or I) are of a compelling significance in the generation of nuclear energy and waste storage. Because of their physiochemical properties, Porous Organic Polymers (POPs) are considered to be one of the most sought classes of materials for iodine capture and storage. Herein, we report on the preparation and characterization of two triazine-based, nitrogen-rich, porous organic polymers, NRPOP-1 (SA = 519 m g) and NRPOP-2 (SA = 456 m g), by reacting 1,3,5-triazine-2,4,6-triamine or 1,4-bis-(2,4-diamino-1,3,5-triazine)-benzene with thieno[2,3-b]thiophene-2,5-dicarboxaldehyde, respectively, and their use in the capture of volatile iodine. NRPOP-1 and NRPOP-2 showed a high adsorption capacity of iodine vapor with an uptake of up to 317 wt % at 80 °C and 1 bar and adequate recyclability. The NRPOPs were also capable of removing up to 87% of iodine from 300 mg L iodine-cyclohexane solution. Furthermore, the iodine-loaded polymers, I@NRPOP-1 and I@NRPOP-2, displayed good antibacterial activity against Micrococcus luteus (ML), Escherichia coli (EC), and Pseudomonas aeruginosa (PSA). The synergic functionality of these novel polymers makes them promising materials to the environment and public health.
Topics: Adsorption; Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Storage; Escherichia coli; Iodine Radioisotopes; Micrococcus luteus; Nitrogen; Organic Chemicals; Polymers; Porosity; Triazines; Volatilization
PubMed: 35173259
DOI: 10.1038/s41598-022-06671-0 -
International Journal of Molecular... May 2022Pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer...
Pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine sulfonamides constitute a novel class of heterocyclic compounds with broad biological activity, including anticancer properties. Investigated in this study, MM-compounds (, , , and ) exhibited cytotoxic and proapoptotic activity against cancer cell lines (BxPC-3, PC-3, and HCT-116) in nanomolar concentrations without causing cytotoxicity in normal cells (L929 and WI38). In silico predictions indicate that tested compounds exhibit favorable pharmacokinetic profiles and may exert anticancer activity through the inhibition of BTK kinase, the AKT-mTOR pathway and PD1-PD-L1 interaction. Our findings point out that these sulfonamide derivatives may constitute a source of new anticancer drugs after optimization.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Molecular Structure; Structure-Activity Relationship; Sulfonamides; Triazines
PubMed: 35682571
DOI: 10.3390/ijms23115892 -
International Journal of Molecular... Mar 2023The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise... (Review)
Review
The anti-epileptic drug lamotrigine (LTG) has been widely used to treat various neurological disorders, including epilepsy and bipolar disorder. However, its precise mechanism of action in the central nervous system (CNS) still needs to be determined. Recent studies have highlighted the involvement of LTG in modulating the activity of voltage-gated ion channels, particularly those related to the inhibition of neuronal excitability. Additionally, LTG has been found to have neuroprotective effects, potentially through the inhibition of glutamate release and the enhancement of GABAergic neurotransmission. LTG's unique mechanism of action compared to other anti-epileptic drugs has led to the investigation of its use in treating other CNS disorders, such as neuropathic pain, PTSD, and major depressive disorder. Furthermore, the drug has been combined with other anti-epileptic drugs and mood stabilizers, which may enhance its therapeutic effects. In conclusion, LTG's potential to modulate multiple neurotransmitters and ion channels in the CNS makes it a promising drug for treating various neurological disorders. As our understanding of its mechanism of action in the CNS continues to evolve, the potential for the drug to be used in new indications will also be explored.
Topics: Humans; Lamotrigine; Depressive Disorder, Major; Anticonvulsants; Epilepsy; Central Nervous System; Glutamic Acid; Ion Channels; Triazines
PubMed: 37047022
DOI: 10.3390/ijms24076050 -
Asia Pacific Journal of Clinical... Dec 2016The melamine contaminated milk powder contamination scandal occurred in China in 2008. Its main consequences so far have been urinary stone formation in children with... (Review)
Review
The melamine contaminated milk powder contamination scandal occurred in China in 2008. Its main consequences so far have been urinary stone formation in children with associated renal damage and increased child mortality. Eight years have passed, but food safety issues still remain of concern in the daily lives of millions of Chinese. Vigilance is required to ensure no recurrence of such food safety problems. Ongoing studies focus on the early detection of food industry malpractice, mechanisms whereby these toxic substances induce disease and how its advent may be prevented and better managed. Melamine undergoes renal excretion, but is metabolized slowly and excreted largely unchanged in the urine. Urinary melamine measurement may provide a rapid and inexpensive way to identify exposure to melamine adulterated food items. Although most patients with melaminerelated urinary stones (MUS) have been responsive to conservative treatment, longer time follow-up is needed to assess chronic effects. Aside from MUS, melamine is a recognized carcinogen and can induce urinary tract tumours. Very little is known about the effects of excessive exposure to melamine contaminated milk powder in infants on growth, adolescent and adult health, although short-term effects have become apparent during the scandal.
Topics: Animals; Carcinogens; China; Food Contamination; Food Safety; Food, Preserved; Kidney Diseases; Milk; Triazines; Urinary Calculi; Urologic Neoplasms
PubMed: 27702712
DOI: 10.6133/apjcn.072016.01 -
Molecules (Basel, Switzerland) Apr 2022Chlrosulfuron, a classical sulfonylurea herbicide that exhibits good safety for wheat but causes a certain degree of damage to subsequent corn in a wheat-corn rotation...
Chlrosulfuron, a classical sulfonylurea herbicide that exhibits good safety for wheat but causes a certain degree of damage to subsequent corn in a wheat-corn rotation mode, has been suspended field application in China since 2014. Our previous study found that diethylamino-substituted chlorsulfuron derivatives accelerated the degradation rate in soil. In order to obtain sulfonylurea herbicides with good crop safety for both wheat and corn, while maintaining high herbicidal activities, a series of pyrimidine- and triazine-based diethylamino-substituted chlorsulfuron derivatives (-) were systematically evaluated. The structures of the synthesized compounds were confirmed with H NMR, C NMR, and HRMS. The preliminary biological assay results indicate that the 4,6-disubstituted pyrimidine and triazine derivatives could maintain high herbicidal activity. It was found that the synthesized compounds could accelerate degradation rates, both in acidic and alkaline soil. Especially, in alkaline soil, the degradation rate of the target compounds accelerated more than 22-fold compared to chlorsulfuron. Moreover, most chlorsulfuron analogs exhibited good crop safety for both wheat and corn at high dosages. This study provided a reference for the further design of new sulfonylurea herbicides with high herbicidal activity, fast degradation rates, and high crop safety.
Topics: Herbicides; Pyrimidines; Soil; Structure-Activity Relationship; Sulfonamides; Sulfonylurea Compounds; Triazines; Zea mays
PubMed: 35408768
DOI: 10.3390/molecules27072362 -
Chemosphere Jul 2018The herbicide terbuthylazine (TBA) has displaced atrazine in most of EU countries, becoming one of the most regularly used pesticides and, therefore, frequently detected... (Review)
Review
The herbicide terbuthylazine (TBA) has displaced atrazine in most of EU countries, becoming one of the most regularly used pesticides and, therefore, frequently detected in natural waters. The affinity of TBA for soil organic matter suggests prolonged contamination; degradation leads to the release of the metabolite desethylterbuthylazine (DET), which has higher water solubility and binds more weakly to organic matter compared to the parent compound, resulting in higher associated risk for contamination of groundwater resources. Additionally, TBA and DET are chemicals of emerging concern because of their persistence and toxicity towards aquatic organisms; moreover, they are known to have significant endocrine disruption capacity to wildlife and humans. Conventional treatments applied during drinking water production do not lead to the complete removal of these chemicals; activated carbon provides the greatest efficiency, whereas ozonation can generate by-products with comparable oestrogenic activity to atrazine. Hydrogen peroxide alone is ineffective to degrade TBA, while UV/HO advanced oxidation and photocatalysis are the most effective processes for oxidation of TBA. It has been determined that direct photolysis gives the highest degradation efficiency of all UV/HO treatments, while most of the photocatalytic degradation is attributed to OH radicals, and TiO solar-photocatalytic ozonation can lead to almost complete TBA removal in ∼30 min. Constructed wetlands provide a valuable buffer capacity, protecting downstream surface waters from contaminated runoff. TBA and DET occurrence are summarized and removal techniques are critically evaluated and compared, to provide the reader with a comprehensive guide to state-of-the-art TBA removal and potential future treatments.
Topics: Herbicides; Hydrogen Peroxide; Oxidation-Reduction; Photolysis; Triazines; Water Pollutants, Chemical
PubMed: 29554512
DOI: 10.1016/j.chemosphere.2018.03.091 -
International Journal of Molecular... Apr 2017The large-scale simultaneous extraction and concentration of aqueous solutions of triazine analogs, and aflatoxins, through a hydrocarbon-based membrane (e.g.,...
The large-scale simultaneous extraction and concentration of aqueous solutions of triazine analogs, and aflatoxins, through a hydrocarbon-based membrane (e.g., polyethylene, polyethylene/polypropylene copolymer) under ambient temperature and atmospheric pressure is reported. The subsequent adsorption of analyte in the extraction chamber over the lignin-modified silica gel facilitates the process by reducing the operating time. The maximum adsorption capacity values for triazine analogs and aflatoxins are mainly adsorption mechanism-dependent and were calculated to be 0.432 and 0.297 mg/10 mg, respectively. The permeation, and therefore the percentage of analyte extracted, ranges from 1% to almost 100%, and varies among the solvents examined. It is considered to be vapor pressure- and chemical polarity-dependent, and is thus highly affected by the nature and thickness of the membrane, the discrepancy in the solubility values of the analyte between the two liquid phases, and the amount of adsorbent used in the process. A dependence on the size of the analyte was observed in the adsorption capacity measurement, but not in the extraction process. The theoretical interaction simulation and FTIR data show that the planar aflatoxin molecule releases much more energy when facing toward the membrane molecule when approaching it, and the mechanism leading to the adsorption.
Topics: Adsorption; Aflatoxins; Chemistry Techniques, Analytical; Chromatography, High Pressure Liquid; Hydrocarbons; Lignin; Membranes, Artificial; Polyethylene; Polypropylenes; Silica Gel; Solubility; Solvents; Spectroscopy, Fourier Transform Infrared; Triazines; Viscosity
PubMed: 28398252
DOI: 10.3390/ijms18040801 -
Drugs Feb 2021Imeglimin is the first of the "glimins," a new class of drugs developed for the treatment of type 2 diabetes mellitus (T2DM). This review highlights its mechanism of... (Review)
Review
Imeglimin is the first of the "glimins," a new class of drugs developed for the treatment of type 2 diabetes mellitus (T2DM). This review highlights its mechanism of action and its context in the field of T2DM treatment. Preclinical data in multiple rodent models have detailed significant effects on mitochondria, particularly improved mitochondrial bioenergetics. This includes changes favoring complex II and complex III metabolism, a mechanism potentially promoting increased fatty acid oxidation, leading to the decrease in hepatic lipid accumulation observed in these mice. Imeglimin was also shown to increase muscle glucose uptake and decrease hepatic glucose production, both in vitro and in vivo. Though studies have also shown imeglimin to significantly improve insulin secretion and decrease β-cell death, whether its physiologic effects are purely insulin dependent remains unclear. Early preclinical studies have shown evidence for improvements in cardiac and renal function in rats with metabolic syndrome, effects not conferred by most currently available T2DM drugs. Clinical studies of imeglimin in humans have shown increased insulin secretion, along with decreased fasting plasma glucose and glycated hemoglobin. Its observed efficacy was comparable to that of currently available agents metformin and sitagliptin and was increased when given in combination with either agent. When considered alongside its benign safety profile reported in patients with chronic kidney disease, imeglimin shows true promise to provide a novel mechanism for T2DM treatment, with potential application in a larger, more comprehensive patient population.
Topics: Diabetes Mellitus, Type 2; Drug Development; Humans; Hypoglycemic Agents; Triazines
PubMed: 33247829
DOI: 10.1007/s40265-020-01434-5 -
Molecules (Basel, Switzerland) Aug 2020This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-][1,2,4]triazine derivatives against different tumor cell lines. Some annulated... (Review)
Review
This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3-][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3-][1,2,4]triazolo[4,3-][1,2,4]triazines and pyrazolo[4,3-]tetrazolo[1,5-][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, which could have excellent potential to be new candidate therapeutic agents in cancer chemotherapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Triazines
PubMed: 32872493
DOI: 10.3390/molecules25173948