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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 -
Journal of Agricultural and Food... Jun 2024Celangulin V is a novel botanical insecticide with significant bioactivity and a unique molecular target, but its complex polyol ester structure hinders its broader...
Celangulin V is a novel botanical insecticide with significant bioactivity and a unique molecular target, but its complex polyol ester structure hinders its broader application in agriculture. To discover new analogues of celangulin V with a simpler structure and enhanced biological activities, we initiated a research project aimed at simplifying its structure and assessing insecticidal efficacy. In this study, a series of novel 1-tetralone derivatives were designed via a structure-based rational design approach and synthesized by a facile method. The biological activities of the target compounds were determined against (), , and . The results revealed that most of the synthesized compounds exhibited superior activities compared to celangulin V. Remarkably, the insecticidal activity of compound demonstrated 102-fold greater stomach toxicity than celangulin V against . In addition, certain compounds showed significant contact toxicity against , a finding not reported previously in the structural optimization studies of celangulin V. Molecular docking analysis illustrated that the binding pocket of compound with the H subunit of V-ATPase was the same as celangulin V. This study presents novel insights into the structural optimization of botanical pesticides.
PubMed: 38926152
DOI: 10.1021/acs.jafc.4c01079 -
Discovery Medicine Jun 2024Cutaneous melanoma is a malignant tumor with an increasing incidence, prone to recurrence and metastasis. This study aims to explore the effects and mechanisms of the...
BACKGROUND
Cutaneous melanoma is a malignant tumor with an increasing incidence, prone to recurrence and metastasis. This study aims to explore the effects and mechanisms of the novel shikonin derivative 5,8-dimethyl alkannin oxime derivative (DMAKO-20) on the metastasis and invasion of melanoma cells.
METHODS
The inhibitory effects of DMAKO-20 on the melanoma cell line A375 were investigated through Cell Counting Kit-8 (CCK-8), Transwell and angiogenesis experiments. Network pharmacology and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to explore potential sites and pathways involved in this process. Additionally, quantitative polymerase chain reaction (qPCR) and Western blot experiments were conducted before and after drug treatment to verify the expression trends of related pathways and proteins.
RESULTS
DMAKO-20 demonstrated selective inhibition of proliferation, invasion and migration of melanoma cells at low concentrations. The WNT pathway appears to be implicated in this process, as DMAKO-20 effectively attenuates its activation, consequently reducing matrix metalloproteinase 9 (MMP9) and Cellular Communication Network Factor 1 (CCN1)/cysteine-rich angiogenic inducer 61 (CYR61) levels. Such modulation inhibits melanoma dissemination and invasion into other tissues.
CONCLUSION
DMAKO-20 exhibits the capability to suppress metastasis and invasion of melanoma cells, suggesting its potential for clinical application as an adjuvant therapy against melanoma.
Topics: Humans; Naphthoquinones; Melanoma; Cell Line, Tumor; Neoplasm Invasiveness; Cell Movement; Cell Proliferation; Neoplasm Metastasis; Wnt Signaling Pathway; Skin Neoplasms; Gene Expression Regulation, Neoplastic; Melanoma, Cutaneous Malignant
PubMed: 38926109
DOI: 10.24976/Discov.Med.202436185.113 -
Journal of Agricultural and Food... Jun 2024In recent decades, the unique structural attributes and purported insecticidal properties of oximes have garnered increasing attention. A variety of insecticides,... (Review)
Review
In recent decades, the unique structural attributes and purported insecticidal properties of oximes have garnered increasing attention. A variety of insecticides, encompassing fluxametamide, fluhexafon, and lepimectin, have been synthesized, all of which incorporate oximes. This review endeavors to encapsulate the insecticidal efficacy, structure-activity correlations, and operative mechanisms of oxime-containing compounds. Furthermore, it delves into the conceptual frameworks underpinning the design of innovative oxime-based insecticides, thereby shedding light on prospective advancements in this field.
PubMed: 38920088
DOI: 10.1021/acs.jafc.4c02096 -
Chemical Communications (Cambridge,... Jun 2024The oxime functional group is pivotal in chemistry, finding extensive applications in medical science, catalysis, organic functional group transformations, and the... (Review)
Review
The oxime functional group is pivotal in chemistry, finding extensive applications in medical science, catalysis, organic functional group transformations, and the recognition of essential and toxic analytes. While the coordination chemistry of oxime derivatives has been thoroughly explored and several reviews have been published on this topic in reputable journals, a comprehensive review encompassing various aspects such as crystal engineering, cation and anion recognition, as well as coordination chemistry activities, is still in demand. This feature article highlights the diverse applications of oxime derivatives across multiple domains of chemistry, including medicine, agriculture, crystal engineering, coordination chemistry, and molecular recognition studies. Each of the oxime derivatives in this feature article are meticulously described in terms of their medicinal applications, crop protection, crystal engineering attributes, analyte recognition capabilities, and coordination chemistry aspects. By providing a comprehensive overview of their versatile applications, this article aims to inspire researchers to explore and develop novel oxime-based derivatives for future applications.
PubMed: 38916274
DOI: 10.1039/d4cc01397b -
Materials Horizons Jun 2024It is challenging for ionic liquid gels to achieve the combination of rapid self-healing with high toughness. Here, ionic liquid gels (DI-PR) were prepared from readily...
It is challenging for ionic liquid gels to achieve the combination of rapid self-healing with high toughness. Here, ionic liquid gels (DI-PR) were prepared from readily available materials. A dynamic covalently bonded oxime-carbamate was prepared from polycaprolactone diol, isophorone diisocyanate and dimethylethyleneglyoxime, followed by addition of the "rigid-flexible" cross-linking agent rutin to chemically cross-link the polymer chains and afford the ionic liquid gels, DI-PR. The tensile strength, elongation at break and toughness of the DI-PR gels were as high as 16.5 MPa, 1132.6%, and 52.6 MJ m, respectively. The toughness is similar to that of natural silkworm silk (70 MJ m) and wool (60 MJ m). After stretching, the DI-PR can rebound within 1 s, their room temperature self-healing rate is as high as 92%, they remain functional over the temperature range -50 °C to 140 °C and the interface with a steel plate has an adhesion toughness of >2000 J m. These properties mean that the DI-PR gels are particularly suitable for use as anticorrosion coatings for submarine and underground gas and oil pipelines. The use of rutin, which combines rigid quercetin-based structural units with flexible glycoside-based structural units, as a cross-linking agent, provides a new method for improving the toughness of soft materials through its synergistic interaction with hard and soft chain fragments of polyurethanes.
PubMed: 38910542
DOI: 10.1039/d4mh00497c -
ACS Medicinal Chemistry Letters Jun 2024In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested for...
In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative , which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An study was conducted to assess the binding mode of within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.
PubMed: 38894925
DOI: 10.1021/acsmedchemlett.4c00206 -
Photochemical & Photobiological... Jun 2024Photoisomerization is a key photochemical reaction in microbial and animal rhodopsins. It is well established that such photoisomerization is highly selective; all-trans...
Photoisomerization is a key photochemical reaction in microbial and animal rhodopsins. It is well established that such photoisomerization is highly selective; all-trans to 13-cis, and 11-cis to all-trans forms in microbial and animal rhodopsins, respectively. Nevertheless, unusual photoisomerization pathways have been discovered recently in microbial rhodopsins. In an enzymerhodopsin NeoR, the all-trans chromophore is isomerized into the 7-cis form exclusively, which is stable at room temperature. Although, the 7-cis form is produced by illumination of retinal, formation of the 7-cis form was never reported for a protonated Schiff base of all-trans retinal in solution. Present HPLC analysis of retinal oximes prepared by hydroxylamine reaction revealed that all-trans and 7-cis forms cannot be separated from the syn peaks under the standard HPLC conditions, while it is possible by the analysis of the anti-peaks. Consequently, we found formation of the 7-cis form by the photoreaction of all-trans chromophore in solution, regardless of the protonation state of the Schiff base. Upon light absorption of all-trans protonated retinal Schiff base in solution, excited-state relaxation accompanies double-bond isomerization, producing 7-cis, 9-cis, 11-cis, or 13-cis form. In contrast, specific chromophore-protein interaction enforces selective isomerization into the 13-cis form in many microbial rhodopsins, but into 7-cis in NeoR.
PubMed: 38886314
DOI: 10.1007/s43630-024-00602-w -
Bioorganic Chemistry Jun 2024In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of... (Review)
Review
In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of these reactivators are critically discussed. Organophosphorus compounds such as nerve agents (sarin, tabun, VX) or pesticides (chlorpyrifos, diazinon) cause irreversible inhibition of acetylcholinesterase (AChE) and BChE in the human body. While AChE inhibition can be life threatening due to cholinergic overstimulation and crisis, selective BChE inhibition has presumably no adverse effects. Because BChE is mostly found in plasma, its activity is important for the scavenging of organophosphates before they can reach AChE in the central nervous system. Therefore, this enzyme in combination with its reactivator can be used as a pseudo-catalytic scavenger of organophosphates. Three structural types of BChE reactivators were found, i.e. bisquaternary salts, monoquaternary salts and uncharged compounds. Although the reviewed reactivators have certain limitations, the promising candidates for BChE reactivation were found in each structural group.
PubMed: 38878749
DOI: 10.1016/j.bioorg.2024.107526 -
Angewandte Chemie (International Ed. in... Jun 2024In this work, six benzothioxanthene-based oxime esters were employed as photoinitiators for photopolymerization with visible light (LED) and sunlight. Their abilities to...
High Photoinitiating Efficiency of Benzothioxanthene-based Oxime Esters in Photopolymerization via Photocleavage and/or Single Electron Transfer under Visible Light and Sunlight.
In this work, six benzothioxanthene-based oxime esters were employed as photoinitiators for photopolymerization with visible light (LED) and sunlight. Their abilities to behave as Type I photoinitiators by mean of a photocleavage mechanism of oxime esters but also in multicomponent photoinitiating system with an iodonium salt (through an electron transfer mechanism) were both explored with the different structures. Due to their broad absorption spectra tailing up 600 nm, photoinitiating properties of the benzothioxanthene-based oxime esters were systematically tested under excitation with low-intensity LED light at wavelengths of 405 nm and 450 nm. Additionally, to the polymerization tests done under artificial light, different benzothioxanthene-based oxime esters were also investigated as solar photoinitiators and displayed a high reactivity in France (Western Europe) even in winter conditions. For the best candidates i.e. the most reactive structures, direct laser write experiments were carried out, evidencing the interest of these structures.
PubMed: 38877857
DOI: 10.1002/anie.202405337