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Cell Reports. Medicine May 2023Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the...
Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.
Topics: Animals; Mice; Glioblastoma; Tryptophan; Kynurenine; Oximes
PubMed: 37060903
DOI: 10.1016/j.xcrm.2023.101019 -
The Journal of Organic Chemistry May 2024Introducing glycans represents an efficient chemical approach to improve the pharmacological properties of therapeutic biomolecules. Herein, we report an efficient...
Introducing glycans represents an efficient chemical approach to improve the pharmacological properties of therapeutic biomolecules. Herein, we report an efficient synthesis of glycoconjugates through chlorooxime-thiol conjugation. The reactive glycosyl chlorooximes, derived from pyranoses or furanoses, readily couple to a wide range of thiol-containing substrates, including peptides, sugars, and thiophenols. This method features mild reaction conditions and fast kinetics. Capability for aqueous media and gram-scale synthesis demonstrates the potential of this method in the bioconjugation of saccharides with biologically active molecules.
Topics: Oximes; Glycoconjugates; Sulfhydryl Compounds; Molecular Structure
PubMed: 38650458
DOI: 10.1021/acs.joc.4c00356 -
International Journal of Molecular... Nov 2022Seven pyridoxal dioxime quaternary salts (-) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and...
Seven pyridoxal dioxime quaternary salts (-) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The synthesis was achieved by the quaternization of pyridoxal monooxime with substituted 2-bromoacetophenone oximes (phenacyl bromide oximes). All compounds, prepared in good yields (43-76%) and characterized by 1D and 2D NMR spectroscopy, were evaluated as reversible inhibitors of cholinesterase and/or reactivators of enzymes inhibited by toxic organophosphorus compounds. Their potency was compared with that of their monooxime analogues and medically approved oxime HI-6. The obtained pyridoxal dioximes were relatively weak inhibitors for both enzymes ( = 100-400 µM). The second oxime group in the structure did not improve the binding compared to the monooxime analogues. The same was observed for reactivation of VX-, tabun-, and paraoxon-inhibited AChE and BChE, where no significant efficiency burst was noted. In silico analysis and molecular docking studies connected the kinetic data to the structural features of the tested compound, showing that the low binding affinity and reactivation efficacy may be a consequence of a bulk structure hindering important reactive groups. The tested dioximes were non-toxic to human neuroblastoma cells (SH-SY5Y) and human embryonal kidney cells (HEK293).
Topics: Humans; Butyrylcholinesterase; Acetylcholinesterase; Cholinesterase Reactivators; Molecular Docking Simulation; Cholinesterase Inhibitors; HEK293 Cells; Neuroblastoma; Oximes; Pyridoxal; Ligands
PubMed: 36362178
DOI: 10.3390/ijms232113388 -
Chembiochem : a European Journal of... Sep 20222-(Aminooxy)-N-(quinolin-8-yl)acetamide was synthesized, and its ability to regulate activities of DNA polymerase was tested. In addition, we used the isothermal...
2-(Aminooxy)-N-(quinolin-8-yl)acetamide was synthesized, and its ability to regulate activities of DNA polymerase was tested. In addition, we used the isothermal amplification technology to detect the content of 5-formyluracil sites in irradiated genomic DNA, which confirmed its capability for the detection of 5-formyluracil content in general samples. This study presents the first example of the determination of 5fU based on coordination chemistry.
Topics: Acetamides; DNA; Fluorouracil; Nucleotides; Oximes; Uracil
PubMed: 35849116
DOI: 10.1002/cbic.202200355 -
Molecules (Basel, Switzerland) Sep 2021c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and...
c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11-indeno[1,2-]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds ( and ) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.
Topics: Anti-Inflammatory Agents; Biological Availability; Cell Line; Humans; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Monocytes; Oximes; Protein Isoforms; Protein Kinase Inhibitors; Quinoxalines
PubMed: 34577159
DOI: 10.3390/molecules26185688 -
Biomaterials Apr 2021Vitreous substitutes are clinically used to maintain retinal apposition and preserve retinal function; yet the most used substitutes are gases and oils which have...
Vitreous substitutes are clinically used to maintain retinal apposition and preserve retinal function; yet the most used substitutes are gases and oils which have disadvantages including strict face-down positioning post-surgery and the need for subsequent surgical removal, respectively. We have engineered a vitreous substitute comprised of a novel hyaluronan-oxime crosslinked hydrogel. Hyaluronan, which is naturally abundant in the vitreous of the eye, is chemically modified to crosslink with poly(ethylene glycol)-tetraoxyamine via oxime chemistry to produce a vitreous substitute that has similar physical properties to the native vitreous including refractive index, density and transparency. The oxime hydrogel is cytocompatible in vitro with photoreceptors from mouse retinal explants and biocompatible in rabbit eyes as determined by histology of the inner nuclear layer and photoreceptors in the outer nuclear layer. The ocular pressure in the rabbit eyes was consistent over 56 d, demonstrating limited to no swelling. Our vitreous substitute was stable in vivo over 28 d after which it began to degrade, with approximately 50% loss by day 56. We confirmed that the implanted hydrogel did not impact retina function using electroretinography over 90 days versus eyes injected with balanced saline solution. This new oxime hydrogel provides a significant improvement over the status quo as a vitreous substitute.
Topics: Animals; Biomimetics; Hyaluronic Acid; Hydrogels; Mice; Oximes; Rabbits; Retina; Vitreous Body
PubMed: 33725584
DOI: 10.1016/j.biomaterials.2021.120750 -
Scientific Reports Dec 2019In present investigation, an attempt was undertaken to modify the C-9 position of noscapine (Nos), an opium alkaloid to yield 9 -hydroxy methyl and 9 -carbaldehyde oxime...
In present investigation, an attempt was undertaken to modify the C-9 position of noscapine (Nos), an opium alkaloid to yield 9 -hydroxy methyl and 9 -carbaldehyde oxime analogues for augmenting anticancer potential. The synthesis of 9-hydroxy methyl analogue of Nos was carried out by Blanc reaction and 9-carbaldehyde oxime was engineered by oxime formation method and characterized using FT-IR, H NMR, C NMR, mass spectroscopy, and so on techniques. In silico docking techniques informed that 9-hydroxy methyl and 9-carbaldehyde oxime analogues of Nos had higher binding energy score as compared to Nos. The IC50 of Nos was estimated to be 46.8 µM signficantly (P < 0.05) higher than 8.2 µM of 9-carbaldehyde oxime and 4.6 µM of 9-hydroxy methyl analogue of Nos in U87, human glioblastoma cells. Moreover, there was significant (P < 0.05) difference between the IC50 of 9-carbaldehyde oxime and 9-hydroxy methyl analogue of Nos. Consistent to in vitro cytotoxicity data, 9-hydroxy methyl analogue of Nos induced significantly (P < 0.05) higher degree of apoptosis of 84.6% in U87 cells as compared to 78.5% and 64.3% demonstrated by 9-carbaldehyde oxime and Nos, respectively. Thus the higher therapeutic efficacy of 9-hydroxy methyl analogue of Nos may be credited to higher solubility and inhibitory constant (K).
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Magnetic Resonance Spectroscopy; Microtubules; Noscapine; Oximes; Spectroscopy, Fourier Transform Infrared
PubMed: 31862933
DOI: 10.1038/s41598-019-55839-8 -
Topics in Current Chemistry (Cham) May 2023Oxime esters as the applicable building blocks, internal oxidizing agents, and directing groups in the synthesis of -, S-, and O-containing heterocycle scaffolds have... (Review)
Review
Oxime esters as the applicable building blocks, internal oxidizing agents, and directing groups in the synthesis of -, S-, and O-containing heterocycle scaffolds have gained great attention in the last decade. This review provides an overview of recent advances in the cyclization of oxime esters with various functional group reagents under transition metal and transition metal-free catalyzed conditions. Moreover, the mechanistic aspects of these protocols are explained in detail.
Topics: Molecular Structure; Oximes; Esters; Catalysis; Transition Elements
PubMed: 37202650
DOI: 10.1007/s41061-023-00431-y -
Molecules (Basel, Switzerland) Feb 2023Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which... (Review)
Review
Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods.
Topics: Oximes; Hydroxylamines; Catalysis; Cyclization; Nitrogen
PubMed: 36838760
DOI: 10.3390/molecules28041775 -
Bioorganic Chemistry Oct 2019We reported an useful protocol for the labeling of the second domain of the Vascular Endothelial Growth Factor Receptor 1 (VEGFR1D2), a small protein ligand able to bind...
We reported an useful protocol for the labeling of the second domain of the Vascular Endothelial Growth Factor Receptor 1 (VEGFR1D2), a small protein ligand able to bind VEGF, the main regulator of angiogenesis. We developed a bioconjugation strategy based on the use of oxime-ligation reaction conjugating an aldehyde derivative of the VEGFR1D2 to a molecular probe harboring an alkoxyamine functional group. We applied the synthetic protocol to prepare a biotinylated conjugate of VEGFR1D2 and we demonstrate that the bioconjugate retains its ability to specifically bind its natural ligand, VEGF, with high affinity. The biotinylated VEGFR1D2 could be useful to detect and quantify VEGF for diagnostic purposes as well as a tool for the screening of new molecules targeting VEGFRs for therapeutic applications. The labeling protocol is versatile and can be extended to different molecular probes, such as fluorophores, chelators or multimeric scaffolds, affording a biomedical platform for VEGF targeting.
Topics: Aldehydes; Humans; Ligands; Oximes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 31398600
DOI: 10.1016/j.bioorg.2019.103160