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Drug Metabolism Reviews Nov 2023Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated... (Review)
Review
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (C) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher C, AUC and half-life (t) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.
Topics: Male; Humans; Nebivolol; Hypertension; Fluvoxamine; Lansoprazole; Drug Interactions
PubMed: 37849071
DOI: 10.1080/03602532.2023.2271195 -
Molecules (Basel, Switzerland) Dec 2023Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery.... (Review)
Review
Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody-drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl-alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.
Topics: Antibodies; Immunoconjugates; Antigens; Drug Delivery Systems; Antineoplastic Agents
PubMed: 38067618
DOI: 10.3390/molecules28237890 -
Accounts of Chemical Research Nov 2023ConspectusElastomers have been extensively used in diverse industrial sectors such as footwear, seals, tires, and cable jacketing and have attracted more and more...
ConspectusElastomers have been extensively used in diverse industrial sectors such as footwear, seals, tires, and cable jacketing and have attracted more and more attention in emerging fields such as regenerative medicine, soft robotics, and stretchable electronics. Global consumption of natural and synthetic elastomers amounted to nearly 27 million metric tons in 2020. In addition, to further enhance the common properties of elastomers, it is highly desired to endow elastomers with functionalities such as reprocessability, biomimetic mechanical properties, self-healing ability, bioactivity, and electrical conductivity, which will significantly broaden their applications. The covalent or noncovalent cross-linked structure is the essential factor for the elasticity of elastomers. Traditional elastomers usually comprise a single type of cross-linked molecular network, for which it is difficult to modulate the properties and introduce functionalities. Inspired by the simultaneous existence of multiple cross-linked structures in proteins, researchers have employed a hybrid cross-linking strategy to construct elastomers. Various noncovalent interactions (e.g., hydrogen bonds, metal-ligand coordination, ionic interactions, and chain folding) and dynamic covalent bonds (e.g., disulfide bonds, oxime-urethane bonds, and urea bonds) have been integrated in elastomers. Accordingly, the properties and functionalities of elastomers can be tuned by regulating the types, ratios, and distributions of cross-links. The hybrid cross-linking strategy provides a versatile and effective way to construct diverse functional elastomers for broad applications in various important fields.In this Account, we present our recent progress on functional elastomers constructed by a hybrid cross-linking strategy, including their design, preparation, properties, and diverse applications. First, we provide a brief introduction of the basic concept of functional elastomers and outline general strategies and mechanics for functional elastomers constructed by hybrid cross-linking. Then, we classify hybrid cross-linked elastomers by their design strategies, including multiple cross-linking, topological design, chemical coupling, and multiple networks. The relationships between the functionalities and hybrid cross-linked structures are summarized. At the same time, we also introduce diverse applications of these hybrid cross-linked elastomers in biomedicine, flexible electronics, soft robotics, 3D printing, and so on. Finally, we discuss our perspective on open challenges and future development trends of this rapidly evolving field. This Account highlighting the diverse hybrid cross-linked elastomers not only provides insights into strategies for elastomer functionalization but also provides new ideas for material design and inspires a variety of new applications.
PubMed: 37819099
DOI: 10.1021/acs.accounts.3c00391 -
Natural Product Research May 2024Strong evidence supports the anticancer properties of natural plant product isolates. The cytotoxic, genotoxic, and apoptotic properties of an oxime derivative of...
Strong evidence supports the anticancer properties of natural plant product isolates. The cytotoxic, genotoxic, and apoptotic properties of an oxime derivative of thymoquinone (TQ) in melanoma cancer cells were investigated. The structure of TQ-Oxime was elucidated through nuclear magnetic resonance, and its effect on B16F10 and L929 cell lines was assessed using a luminometric adenosine triphosphate assay. Intracellular reactive oxygen species (iROS) were quantified fluorometry, mitochondrial membrane potential (MMP) was assessed using flow cytometry, glutathione (GSH) levels were measured using a luminometric GSH/oxidized glutathione assay, DNA damage comet assay, and apoptosis was detected using acridine orange/ethidium bromide staining. Concentrations (0.5-20 μM) of TQ-Oxime significantly increased cytotoxicity, DNA damage, apoptosis, and iROS, in a concentration-dependent manner compared ( < 0.001). In addition, MMP and GSH levels decreased significantly with increasing concentrations compared with the control ( < 0.001). Overall, these findings contribute to our understanding of the therapeutic potential of TQ and its derivatives in cancer treatment.
PubMed: 38742473
DOI: 10.1080/14786419.2024.2353913 -
International Journal of Molecular... Nov 2023The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse... (Review)
Review
The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.
Topics: Ether; Oximes; Ethers; Structure-Activity Relationship; Ethyl Ethers
PubMed: 38069175
DOI: 10.3390/ijms242316854 -
Science Advances May 2024State-of-the-art technology for cyclohexanone oxime production typically demands elevated temperature and pressure, along with the utilization of expensive hydroxylamine...
State-of-the-art technology for cyclohexanone oxime production typically demands elevated temperature and pressure, along with the utilization of expensive hydroxylamine sulfate or oxidants. Here, we propose an electrochemistry-assisted cascade strategy for the efficient cyclohexanone ammoximation under ambient conditions by using in situ cathode-generated green oxidants of reactive oxygen species (ROS) such as OOH* and HO. This electrochemical reaction can take place at the cathode, achieving over 95% yield, 99% selectivity of cyclohexanone oxime, and an electron-to-oxime (ETO) efficiency of 96%. Mechanistic analysis reveals that, in addition to the direct ammoximation by in situ-generated OOH* by electrocatalytic ORR, Ti-MOR also play a major role in capturing OOH* directly and converting the in situ-generated HO to OOH*, thus accelerating the ORR-coupled cascade production of cyclohexanone oxime. This work paves a mild, economical, and sustainable energy-efficient electrocatalytic route for the oxime production using oxygen, ammonium bicarbonate, and cyclohexanone.
PubMed: 38787946
DOI: 10.1126/sciadv.ado1755 -
Molecules (Basel, Switzerland) Sep 2023New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds and ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic...
Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.
New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds and ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds -, -, -, and -. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds , , , and inhibited EGFR with IC values ranging from 8 to 21 µM when compared with sorafenib. Compound inhibited JNK-2 as effectively as sorafenib, with an IC of 1.0 µM. Furthermore, compound showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds , , , and exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds and had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.
Topics: Humans; Molecular Docking Simulation; Sorafenib; Structure-Activity Relationship; HeLa Cells; Oximes; Cell Line, Tumor; Antineoplastic Agents; ErbB Receptors; Cell Proliferation; Molecular Structure; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors
PubMed: 37764297
DOI: 10.3390/molecules28186521 -
Nature Reviews. Clinical Oncology Mar 2024In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and... (Review)
Review
In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAF-mutant solid tumours, except for BRAF-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAF-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.
Topics: Adult; Humans; Child; Proto-Oncogene Proteins B-raf; Neoplasms; Imidazoles; Oximes; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38278874
DOI: 10.1038/s41571-023-00852-0 -
Journal of Agricultural and Food... Jul 2023Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel...
Marine natural products have attracted more and more attention in drug research and development due to their unique structure, diverse biological activities, and novel mode of action. Using antiviral alkaloid aldisine as the lead compound and drawing on the hydrogen bond effect widely used in drug design, derivatives containing oxime and hydrazone moieties were designed and synthesized by introducing functional groups with hydrogen-bond receptors or donors into molecules. The configuration of derivatives was systematically studied through nuclear Overhauser effect (NOE) spectroscopy and single crystal analysis. The antiviral activity test result showed that most derivatives had antiviral activity against tobacco mosaic virus (TMV), and some compounds had better activity than the commercial antiviral drug ribavirin, especially compounds and , which had comparable activity to the most effective commercial antiviral drug ningnanmycin. Preliminary mode of action studies showed that compound could affect the assembly of rod-shaped TMVs by promoting the aggregation and fragmentation of TMV coat proteins. Molecular docking experiments demonstrated that the introduction of oxime and hydrazone moieties could indeed increase the hydrogen bond between molecules and target proteins. In addition, we conducted fungicidal and larvicidal activities study of these derivatives. Most of these derivatives had good larvicidal activities against and and showed broad-spectrum fungicidal activities.
Topics: Structure-Activity Relationship; Molecular Structure; Oximes; Molecular Docking Simulation; Hydrogen Bonding; Tobacco Mosaic Virus; Antiviral Agents; Hydrazines; Hydrazones; Drug Design
PubMed: 37442997
DOI: 10.1021/acs.jafc.3c02480