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Natural Product Research Jun 2024In the present study, three series of 35 pyridine-based stilbenes include 10 new compounds prepared by Horner-Wadsworth-Emmons (HWE) reaction were assayed for cytotoxic...
In the present study, three series of 35 pyridine-based stilbenes include 10 new compounds prepared by Horner-Wadsworth-Emmons (HWE) reaction were assayed for cytotoxic activities toward two tumoral cell lines (K562 and MDA-MB-231) and one non-tumoral cell line (L-02). The bioassay results indicated that hybrid stilbenes formed at the C-3 position of pyridine displayed stronger antiproliferative activities against K562 cells and C-4 pyridine-based stilbenes showed broad-spectrum cytotoxic effects. Among them, C-3 pyridine-based stilbene bearing 2,6-dimethoxy possessed extremely potent antiproliferative activity with IC values 1.46 µM against K562 cells, along with excellent selectivity towards normal L-02 cells. In summary, the present study contributes to the development of natural stilbene-based derivatives as antitumor agents and may serve as a promising lead for the treatment of chronic myeloid leukemia (CML) worthy further investigation.
Topics: Stilbenes; Humans; Pyridines; Antineoplastic Agents; K562 Cells; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Molecular Structure; Structure-Activity Relationship
PubMed: 37384584
DOI: 10.1080/14786419.2023.2227991 -
Journal of Hazardous Materials Oct 2023Photosynthetic oxygenation in algal-bacterial symbiotic (ABS) system was mainly concerned to enhance contaminant biodegradation by developing an aerobic environment,...
Photosynthetic oxygenation in algal-bacterial symbiotic (ABS) system was mainly concerned to enhance contaminant biodegradation by developing an aerobic environment, while the role of nitrification-denitrification involved is often neglected. In this study, an algal-bacterial aggregates (ABA) system was developed with algae and activated sludge (PBR-1) to achieve simultaneous pyridine and nitrogen removal. In PBR-1, as high as 150 mg·L pyridine could be completely removed at hydraulic residence time of 48 h. Besides, total nitrogen (TN) removal efficiency could be maintained above 80%. Nitrification-denitrification was verified as the crucial process for nitrogen removal, accounting for 79.3% of TN removal at 180 μmol·m·s. Moreover, simultaneous pyridine and nitrogen removal was enhanced through nitrification-denitrification co-metabolism in the ABA system. Integrated bioprocesses in PBR-1 including photosynthesis, pyridine biodegradation, carbon and nitrogen assimilation, and nitrification-denitrification, were revealed at metabolic and transcriptional levels. Fluorescence in situ hybridization analysis indicated that algae and aerobic species were located in the surface layer, while denitrifiers were situated in the inner layer. Microelectrode analysis confirmed the microenvironment of ABA with dissolved oxygen and pH gradients, which was beneficial for simultaneous pyridine and nitrogen removal. Mechanism of nitrification-denitrification involved in pyridine and nitrogen removal was finally elucidated under the scale of ABA.
Topics: Denitrification; In Situ Hybridization, Fluorescence; Nitrification; Pyridines; Nitrogen
PubMed: 37659235
DOI: 10.1016/j.jhazmat.2023.132390 -
The Journal of Organic Chemistry Jul 2023Thieno[2',3',4':4,5]naphtho[1,8-]pyridines, S,N-doped pyrene analogs, were prepared by combination of Pd catalyzed cross-coupling reactions and acid-mediated...
Thieno[2',3',4':4,5]naphtho[1,8-]pyridines, S,N-doped pyrene analogs, were prepared by combination of Pd catalyzed cross-coupling reactions and acid-mediated cycloisomerization. The modular scope of the synthesis allowed for access to a variety of functionalized derivatives. The photophysical properties have been studied in detail by steady-state and femtosecond transient absorption accompanied by cyclic voltammetry and (TD)-DFT calculations. The introduction of a five-membered thiophene into the 2-azapyrene scaffold leads to redshifted emission and substantial effects on the excited state dynamics, e.g., quantum yield, lifetime, decay rates, and the ISC ability, which can be further tuned by the substitution pattern of the heterocyclic scaffold.
Topics: Pyridines; Molecular Structure; Thiophenes
PubMed: 37279112
DOI: 10.1021/acs.joc.3c00632 -
Chembiochem : a European Journal of... Mar 2024The imidazo[1,2-a]pyridine scaffold has gained significant attention due to its presence as a lead structure in several commercially available pharmaceuticals like...
The imidazo[1,2-a]pyridine scaffold has gained significant attention due to its presence as a lead structure in several commercially available pharmaceuticals like zolimidine, zolpidem, olprinone, soraprazan, etc. Further, indole-based imidazo[1,2-a]pyridine derivatives have been found interesting due to their anticancer and antibacterial activities. However, limited methods have been reported for the synthesis of indole-based imidazo[1,2-a]pyridines. In this study, we have successfully developed a biocatalytic process for synthesizing indole-based imidazo[1,2-a]pyridine derivatives using the α-amylase enzyme catalyzed Groebke-Blackburn-Bienayme (GBB) multicomponent reaction of 2-aminopyridine, indole-3-carboxaldehyde, and isocyanide. The generality and robustness of this protocol were shown by synthesizing differently substituted indole-based imidazo[1,2-a]pyridines in good isolated yields. Furthermore, to make α-amylase a reusable catalyst for GBB multicomponent reaction, it was immobilized onto magnetic metal-organic framework (MOF) materials [Fe O @MIL-100(Fe)] and found reusable up to four consecutive catalytic cycles without the significant loss in catalytic activity.
Topics: alpha-Amylases; Pyridines; Anti-Bacterial Agents; Cyclization; Imidazoles
PubMed: 38279707
DOI: 10.1002/cbic.202300824 -
Bioresource Technology Oct 2023A bottleneck of microalgae-based techniques for wastewater bioremediation is activity inhibition of microalgae by toxic pollutants. The defense strategies of Chlorella...
A bottleneck of microalgae-based techniques for wastewater bioremediation is activity inhibition of microalgae by toxic pollutants. The defense strategies of Chlorella sorokinana against toxic pyridine were studied. Results indicated that pyridine caused photoinhibition and reactive oxygen species overproduction in a concentration-dependent manner. The 50% inhibitory concentration of pyridine (147 mg L) destroyed C/N balance, disrupted multiple metabolic pathways of C. sorokinana. In response to pyridine stress, ascorbate peroxidase and catalase activities increased to scavenge reactive oxygen species under pyridine concentrations lower than 23 mg L. At higher pyridine concentrations, the activation of calcium signaling pathways and phytohormones represented the predominant defense response. Extracellular polymeric substances increased 3.6-fold in 147 mg L group than control, which interacted with pyridine through hydrophobic and aromatic stacking to resist pyridine entering algal cells. Unraveling the intracellular and extracellular self-defense mechanisms of microalgae against pyridine stress facilitates the development of microalgal-based technology in wastewater bioremediation.
Topics: Chlorella; Wastewater; Reactive Oxygen Species; Antioxidants; Pyridines; Microalgae; Biomass
PubMed: 37343803
DOI: 10.1016/j.biortech.2023.129366 -
Virologica Sinica Aug 2023Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral...
Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral gene transcription. The CEN inhibitor, baloxavir marboxil (BXM), was approved in Japan and the US in 2018 and several other countries subsequently. Along with the clinical use of BXM, the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern. Herein, we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A, an analogue of BXM. The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes, including pH1N1, H3N2, H7N9 and H9N2, in MDCK cells, and the 50% effective concentration (EC) was calculated to nanomole level and comparable to that of baloxavir acid (BXA), the active form of BXM. Furthermore, in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice, with reduced viral RNA loads and alleviated pulmonary damage. Importantly, serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage. Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA. Taken together, our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance, which provides critical clues for future drug development and drug resistance surveillance.
Topics: Animals; Mice; Humans; Oxazines; Pyridines; Endonucleases; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Thiepins; Influenza A Virus, H7N9 Subtype; Influenza A Virus, H9N2 Subtype; Antiviral Agents; Influenza, Human; Drug Resistance, Viral
PubMed: 37290559
DOI: 10.1016/j.virs.2023.06.002 -
Journal of Enzyme Inhibition and... Dec 2023Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma...
Herein, a set of pyridine and pyrimidine derivatives were assessed for their impact on the cell cycle and apoptosis. Human breast cancer (MCF7), hepatocellular carcinoma (HEPG2), larynx cancer (HEP2), lung cancer (H460), colon cancers (HCT116 and Caco2), and hypopharyngeal cancer (FADU), and normal Vero cell lines were used. Compounds and displayed outstanding effects on the investigated cell lines and were further tested for their antioxidant activity in MCF7, H460, FADU, HEP2, HEPG2, HCT116, Caco2, and Vero cells by measuring superoxide dismutase (SOD), malondialdehyde content (MDA), reduced glutathione (GSH), and nitric oxide (NO) content. Besides, Annexin V-FITC apoptosis detection and cell cycle DNA index using the HEPG-2 cell line were established on both compounds as well. Furthermore, compounds and were assessed for their EGFR kinase (Wild and T790M) inhibitory activities, revealing eligible potential. Additionally, molecular docking, ADME, and SAR studies were carried out for the investigated candidates.
Topics: Animals; Chlorocebus aethiops; Humans; ErbB Receptors; Protein Kinase Inhibitors; Molecular Docking Simulation; Drug Screening Assays, Antitumor; Vero Cells; Caco-2 Cells; Lung Neoplasms; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Structure-Activity Relationship; Mutation; Pyrimidines; Pyridines; Molecular Structure
PubMed: 36317648
DOI: 10.1080/14756366.2022.2135512 -
Journal of Nuclear Medicine : Official... Sep 2023Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer...
Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer -(4-[F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [F]SNFT-1 using a head-to-head comparison with other reported F-labeled tau tracers. The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [F]SNFT-1. In vitro binding assays demonstrated that [F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, α-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. These preclinical data suggest that [F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.
Topics: Humans; Mice; Animals; Neurodegenerative Diseases; Alzheimer Disease; Pyridines; Brain; tau Proteins; Positron-Emission Tomography
PubMed: 37321821
DOI: 10.2967/jnumed.123.265593 -
A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.United European Gastroenterology Journal Jun 2024Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few... (Review)
Review
Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.
Topics: Humans; Drug Interactions; Inflammatory Bowel Diseases; Piperidines; Pyrimidines; Gastrointestinal Agents; Gastroenterologists; United States Food and Drug Administration; Pyridines; Heterocyclic Compounds, 3-Ring; Indans; Oxadiazoles; Triazoles
PubMed: 38532266
DOI: 10.1002/ueg2.12559 -
Cephalalgia : An International Journal... Apr 2024The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor... (Clinical Trial)
Clinical Trial
BACKGROUND
The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine.
METHODS
This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed ( [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN).
RESULTS
Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified.
CONCLUSIONS
Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified. Clinicaltrials.gov: NCT03266588.
Topics: Humans; Migraine Disorders; Male; Female; Adult; Middle Aged; Pyridines; Piperidines; Calcitonin Gene-Related Peptide Receptor Antagonists; Young Adult; Aged; Adolescent; Treatment Outcome
PubMed: 38659334
DOI: 10.1177/03331024241232944