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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 -
International Journal of Molecular... Jan 2024Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates... (Review)
Review
Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients.
Topics: Humans; Ameloblastoma; Craniopharyngioma; Imidazoles; Oximes; Pituitary Neoplasms
PubMed: 38255797
DOI: 10.3390/ijms25020723 -
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 -
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 -
Actas Dermo-sifiliograficas Oct 2023
Topics: Humans; Darier Disease; Abnormalities, Multiple; Imidazoles; Oximes
PubMed: 35963327
DOI: 10.1016/j.ad.2022.03.019 -
Psychiatry and Clinical Neurosciences Sep 2023The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and anti-depressant properties, on obsessive-compulsive disorder (OCD) symptoms in combination with fluvoxamine.
METHODS
Patients from either sex aged between 18 and 60 years diagnosed with OCD, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of more than 21 were enrolled in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either L-theanine (100 mg twice daily) and fluvoxamine (100 mg daily initially followed by 200 mg daily after week 5) or placebo and fluvoxamine. The primary outcome of interest in this study was the Y-BOCS total score decrease from baseline.
RESULTS
From a total of 95 evaluated patients, 50 completed our study; 30 were randomly assigned to each group. Multivariate analysis (ANOVA) showed a significant effect of time treatment for L-theanine in obsession subscale (F = 5.51, P = 0.008) of the Y-BOCS score but not in the total and compulsion scores. Our results showed significantly more improvement in obsession subscale scores in L-theanine compared to placebo group (P = 0.007, Cohen's d = 0.82). Also, total Y-BOCS scores were lower in L-theanine compared to placebo group at week 5 (P = 0.039, Cohen's d = 0.60) and 10 (P = 0.008, Cohen's d = 0.80). However, there was no significant between-group differences in compulsion subscale scores. Complete response was also more frequent in the L-theanine group (P = 0.0001).
CONCLUSION
Findings in this study suggest L-theanine as a relatively safe and effective adjuvant therapy for moderate to severe OCD.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Fluvoxamine; Selective Serotonin Reuptake Inhibitors; Drug Therapy, Combination; Obsessive-Compulsive Disorder; Glutamates; Double-Blind Method; Treatment Outcome
PubMed: 37169515
DOI: 10.1111/pcn.13565 -
Biomolecules Jun 2024New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous...
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and - [2-(()-2-(5-(()-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.
Topics: Oximes; Cholinesterase Inhibitors; Butyrylcholinesterase; Acetylcholinesterase; Humans; Triazoles; Molecular Docking Simulation; Stilbenes; Cholinesterase Reactivators; Organophosphorus Compounds; Central Nervous System
PubMed: 38927082
DOI: 10.3390/biom14060679 -
Antonie Van Leeuwenhoek Oct 2023Some heterotrophic microorganisms carry out nitrification to produce nitrite and nitrate from pyruvic oxime. Pyruvic oxime dioxygenase (POD) is an enzyme that catalyzes...
Some heterotrophic microorganisms carry out nitrification to produce nitrite and nitrate from pyruvic oxime. Pyruvic oxime dioxygenase (POD) is an enzyme that catalyzes the degradation of pyruvic oxime to pyruvate and nitrite from the heterotrophic nitrifying bacterium Alcaligenes faecalis. Sequence similarity searches revealed the presence of genes encoding proteins homologous to A. faecalis POD in bacteria of the phyla Proteobacteria and Actinobacteria and in fungi of the phylum Ascomycota, and their gene products were confirmed to have POD activity in recombinant experiments. Phylogenetic analysis further classified these POD homologs into three groups. Group 1 POD is mainly found in heterotrophic nitrifying Betaproteobacteria and fungi, and is assumed to be involved in heterotrophic nitrification. It is not clear whether group 2 POD, found mainly in species of the Gammaproteobacteria and Actinobacteria, and group 3 POD, found simultaneously with group 1 POD, are involved in heterotrophic nitrification. The genes of bacterial group 1 POD comprised a single transcription unit with the genes related to the metabolism of aromatic compounds, and many of the genes group 2 POD consisted of a single transcription unit with the gene encoding the protein homologous to 4-hydroxy-tetrahydrodipicolinate synthase (DapA). LysR- or Cro/CI-type regulatory genes were present adjacent to or in the vicinity of these POD gene clusters. POD may be involved not only in nitrification, but also in certain metabolic processes whose functions are currently unknown, in coordination with members of gene clusters.
Topics: Dioxygenases; Phylogeny; Nitrites; Nitrification; Actinobacteria
PubMed: 37596503
DOI: 10.1007/s10482-023-01862-9 -
Structure (London, England : 1993) Dec 2023The cation channel TRPA1 is a potentially important drug target, and characterization of TRPA1 functional dynamics might help guide structure-based drug design. Here, we...
The cation channel TRPA1 is a potentially important drug target, and characterization of TRPA1 functional dynamics might help guide structure-based drug design. Here, we present results from long-timescale molecular dynamics simulations of TRPA1 with an allosteric activator, allyl isothiocyanate (AITC), in which we observed spontaneous transitions from a closed, non-conducting channel conformation into an open, conducting conformation. Based on these transitions, we propose a gating mechanism in which movement of a regulatory TRP-like domain allosterically translates into pore opening in a manner reminiscent of pore opening in voltage-gated ion channels. In subsequent experiments, we found that mutations that disrupt packing of the S4-S5 linker-TRP-like domain and the S5 and S6 helices also affected channel activity. In simulations, we also observed A-967079, a known allosteric inhibitor, binding between helices S5 and S6, suggesting that A-967079 may suppress activity by stabilizing a non-conducting pore conformation-a finding consistent with our proposed gating mechanism.
Topics: Mutation; Oximes; Protein Structure, Secondary
PubMed: 37729917
DOI: 10.1016/j.str.2023.08.018 -
Journal of Biomolecular Structure &... Nov 2023New complexes with the formula of [ML(Cys)(HO)] were obtained as a result of the reaction between the oxime ligand [HL: 4-(4-bromophenylaminoisonitrosoacetyl)biphenyl],...
New complexes with the formula of [ML(Cys)(HO)] were obtained as a result of the reaction between the oxime ligand [HL: 4-(4-bromophenylaminoisonitrosoacetyl)biphenyl], cysteine (Cys), and the metal(II) salts (Mn, Ni, Co, Zn, Cu). The newly synthesized compounds were characterized using conventional techniques such as molar conductance, magnetic measurements, elemental analysis, infrared spectroscopy, and thermal analysis (TGA/DTA). Based on the conductivity measurements in DMF, it was determined that the complexes were non-electrolytes. The TGA/DTA analysis was performed to examine the thermal stability and degradation behavior of all samples, and results demonstrated that metal oxides or sulfides formed as a result of the decompositions. In conjunction with other data obtained, the elemental analysis confirmed the octahedral coordination of the complexes with deprotonated oxime (O, O-donor) and amino acid (N, S-donor) ligands and two coordinated waters. The compounds' optimized geometries, molecular electrostatic potential diagrams, and frontier molecular orbitals were computed at the DFT/B3LYP level using the 6-311 G(d,p) and LANL2DZ basis sets. The antibacterial and DNA cleavage activities of all synthesized compounds were also screened, and molecular docking simulations were performed. According to the results of molecular docking studies conducted with three different proteins, the best interaction was found to be between HL-1HNJ with a binding energy of -9.5 kcal/mol. The stability of the HL-1HNJ complex was also verified by a molecular dynamics simulation performed for 50 ns.Communicated by Ramaswamy H. Sarma.
PubMed: 37968962
DOI: 10.1080/07391102.2023.2281638