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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 -
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 -
Nature May 2024Enzymes play an increasingly important role in improving the benignity and efficiency of chemical production, yet the diversity of their applications lags heavily behind...
Enzymes play an increasingly important role in improving the benignity and efficiency of chemical production, yet the diversity of their applications lags heavily behind chemical catalysts as a result of the relatively narrow range of reaction mechanisms of enzymes. The creation of enzymes containing non-biological functionalities facilitates reaction mechanisms outside nature's canon and paves the way towards fully programmable biocatalysis. Here we present a completely genetically encoded boronic-acid-containing designer enzyme with organocatalytic reactivity not achievable with natural or engineered biocatalysts. This boron enzyme catalyses the kinetic resolution of hydroxyketones by oxime formation, in which crucial interactions with the protein scaffold assist in the catalysis. A directed evolution campaign led to a variant with natural-enzyme-like enantioselectivities for several different substrates. The unique activation mode of the boron enzyme was confirmed using X-ray crystallography, high-resolution mass spectrometry (HRMS) and B NMR spectroscopy. Our study demonstrates that genetic-code expansion can be used to create evolvable enantioselective enzymes that rely on xenobiotic catalytic moieties such as boronic acids and access reaction mechanisms not reachable through catalytic promiscuity of natural or engineered enzymes.
Topics: Biocatalysis; Boronic Acids; Crystallography, X-Ray; Directed Molecular Evolution; Enzymes; Ketones; Kinetics; Models, Molecular; Oximes; Substrate Specificity; Protein Engineering; Nuclear Magnetic Resonance, Biomolecular; Mass Spectrometry; Xenobiotics
PubMed: 38720081
DOI: 10.1038/s41586-024-07391-3 -
Annals of the New York Academy of... Aug 2016Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and... (Review)
Review
Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus.
Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Crystallography, X-Ray; Drug Design; Humans; Organophosphate Poisoning; Oximes; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 27371941
DOI: 10.1111/nyas.13128 -
Scientific Reports Mar 2022Due to market and legislative expectations, there is a constant need to explore new potential antimicrobial agents for functional perfumery. In this study, we evaluated...
Due to market and legislative expectations, there is a constant need to explore new potential antimicrobial agents for functional perfumery. In this study, we evaluated the antimicrobial activity of 53 low molecular oximes and the corresponding carbonyl compounds against Escherichia coli, Enterococcus hirae, Pseudomonas aeruginosa, Bacillus cereus, Staphylococcus aureus, Aspergillus brasiliensis, Legionella pneumophila and Candida albicans. The most potent compound was α-isomethylionone oxime, which exhibited a minimum inhibitory concentration (MIC) of 18.75 µg/mL against E. hirae. The evaluation of the MICs for bacterial and fungal strains was performed for selected compounds, for example, the MIC of 2-phenylpropionaldehyde, cis-jasmone oxime, and trans-cinnamaldehyde measured against A. brasiliensis was 37.50 µg/mL. ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assays were performed to assess the cytotoxicity of tested compounds. ADME-Tox indicated the safety and promising properties of selected compounds, which enables their usage as nontoxic supporting antibacterial agents. The results of the in vitro MTS assay were consistent with the ADME-Tox results. None of the compounds tested was toxic to Human Embryonic Kidney 293T (HEK293T) cells, with all cell viabilities exceeding 85%.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Candida albicans; HEK293 Cells; Humans; Oils, Volatile; Oximes; Plant Extracts
PubMed: 35351944
DOI: 10.1038/s41598-022-09210-z -
Molecules (Basel, Switzerland) Aug 2023Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for...
Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC = 0.06 μM), leading to its selection for further investigation. The direct interactions between compound and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound revealed key interactions between and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.
Topics: Humans; Animals; Mice; STAT3 Transcription Factor; Molecular Docking Simulation; Prospective Studies; Amides; Mice, Inbred BALB C; Naphthoquinones; Oximes
PubMed: 37630387
DOI: 10.3390/molecules28166135 -
Pest Management Science May 2023To study the effect of changing the piperidine ring of oxathiapiprolin on the fungicidal activity, we designed and synthesized novel piperazine thiazole derivatives...
BACKGROUND
To study the effect of changing the piperidine ring of oxathiapiprolin on the fungicidal activity, we designed and synthesized novel piperazine thiazole derivatives containing oxime ether or oxime ester moieties, and studied their fungicidal activities against Phytophthora capsici in vitro.
RESULTS
These derivatives showed moderate to good fungicidal activities against Phytophthora capsici, two oxime ether derivatives showed higher fungicidal activity in vitro than dimethomorph (EC = 0.1331 μg mL ) and comparable to oxathiapiprolin (EC = 0.0042 μg mL ). Oxime ester derivatives showed significantly reduced activities compared with oxime ether derivatives. Most of these derivatives showed broad-spectrum fungicidal activity against the other eight kinds of fungi. Moreover, four derivatives exhibited good antifungal activities in vivo against Phytophthora capsici, Pseudoperonospora cubensis, and Phytophthora infestans. The hyphae morphology study showed that compound 10d might cause mycelial abnormalities of Phytophthora capsici.
CONCLUSION
The activity of 10b against Phytophthora infestans was better than that of mandipropamid, and compound 10d exhibited higher fungicidal activities against Pseudoperonospora cubensis and Phytophthora infestans than mandipropamid. These two derivatives emerged as promising candidates for antifungal drugs. © 2023 Society of Chemical Industry.
Topics: Antifungal Agents; Fungicides, Industrial; Thiazoles; Ether; Esters; Oximes; Ethers; Phytophthora infestans; Ethyl Ethers; Piperazines; Structure-Activity Relationship
PubMed: 36661091
DOI: 10.1002/ps.7374 -
International Journal of Molecular... Oct 2022In the present study, four -substituted oximes of quinuclidin-3-one were synthesized using appropriate -substituted hydroxylamine hydrochlorides. In order to perform...
In the present study, four -substituted oximes of quinuclidin-3-one were synthesized using appropriate -substituted hydroxylamine hydrochlorides. In order to perform these reactions in a solvent, a mixture of () and () products was yielded. Using mechanochemical and microwave synthesis, we then obtained pure () oximes. In almost all cases, the conversion to oxime ethers was completed. Reactions were monitored by ATR spectroscopy and the ratios of () and () oxime ethers were deduced from H NMR data. Several reactions were very rapid (1 min) with 100% conversion and stereospecificity. To investigate the reaction mechanisms, full conformational analyses of the reaction intermediates were performed and the lowest energy conformers were determined. These conformers differed in spatial arrangement around the nitrogen atom of the amino group and were in the correct orientation for reactions to occur. Calculated standard Gibbs energies of the formation were in agreement with the experimentally obtained ratios of ( and () isomers. This work shows alternatives to the classical synthesis of -substituted oxime ether precursors and highlights the fast reaction rate and stereoselectivity of microwave synthesis as well as the "green" aspects of mechanochemistry.
Topics: Oximes; Ether; Ethers; Nitrogen; Solvents
PubMed: 36293187
DOI: 10.3390/ijms232012331 -
Chemistry & Biodiversity Jul 2021In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by...
In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by using anisaldehyde as starting material. Structural characterization of the target compounds was carried out by NMR, FT-IR, ESI-MS, and elemental analysis. Their herbicidal and antifungal activities were preliminarily tested. As a result, at 50 μg/mL, compound (E)-5b exhibited excellent to good inhibition rates of 92.3 %, 79.2 %, and 73.9 %, against Rhizoctonia solani, Fusarium oxysporum f. sp. cucumerinum, and Bipolaris maydis, respectively, better than or comparable to that of the positive control chlorothalonil. In addition, at 100 μg/mL, compounds (E)-5b, (E)-5f, (Z)-5f and (E)-5d exhibited excellent to good inhibition rates of 85.8 %, 82.9 %, 78.6 % and 64.2 %, respectively, against the root-growth of rape (B. campestris), much better than that of the positive control flumioxazin. The bioassay result also showed that the synthesized compounds had obvious differences in antifungal and herbicidal activities between (Z)- and (E)-isomers. Preliminary structure-activity relationship was also discussed by theoretical calculation.
Topics: Antifungal Agents; Benzaldehydes; Bipolaris; Esters; Fusarium; Herbicides; Microbial Sensitivity Tests; Molecular Structure; Oximes; Rhizoctonia; Structure-Activity Relationship
PubMed: 34047003
DOI: 10.1002/cbdv.202100235 -
Organic & Biomolecular Chemistry Jan 2022Seventeen C20--alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC...
Seventeen C20--alkyl/benzyl oxime derivatives were synthesized by a concise and effective method. Most of these derivatives showed tens to several hundred nanomolar IC values against HT-29 colorectal, HGC-27 gastric and MDA-MB-231 breast cancer cells, whose antiproliferative activity is 15-240 fold better than that of salinomycin. The C20-oxime etherified derivatives can coordinate potassium ions, and further adjust the cytosolic Ca concentrations in HT-29 cells. The significant improvement of the potency should be attributed to the better ion binding and transport ability of the modified derivatives. In addition, the C20--alkyl/benzyl oxime derivatives showed much better selectivity indexes (SI) than salinomycin, indicating that they present lower neurotoxic risk.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Conformation; Oximes; Pyrans
PubMed: 35006233
DOI: 10.1039/d1ob02292j