Synthesis and Biological Studies of Novel Aminophosphonates and Their Metal Carbonyl Complexes (Fe, Ru)

Kosińska, Aneta; Virieux, David; Pirat, Jean‐Luc; Czarnecka, Kamila; Girek, Małgorzata; Szymański, Paweł; Wojtulewski, Sławomir; Vasudevan, Saranya; Chworoś, Arkadiusz; Rudolf, Bogna

doi:10.3390/ijms23158091

Cited by 5 publications

(4 citation statements)

References 51 publications

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“…C-terminal amide groups in peptide chains have been discovered to be more resistant to enzymatic degradation and to have conformations that are more suited for interaction with specific receptors, allowing them to be suitable for the syn-thesis of novel peptide analogues [26,27]. Aminophosphonates are gaining increasing research interest as one of the most common organophosphorus derivatives, with various biological activities, including enzyme inhibitors, peptide mimics, antiviral, antibacterial, and anticancer properties, in various applications [28,29]. The N-modified analog of VV-hemorphin-5 bearing an aminophoshonate moiety (V2p) was produced by replacing the two N-terminal Val from the native VV-hemorphin-5 with alpha-aminophosphonate ((dimethoxyphosphoryl)methyl)-L-valine.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents

Todorov,

Assenov,

Angelov

et al. 2023

Biomedicines

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Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study aimed to reveal a detailed picture of the antinociceptive mechanisms and behavioral effects of V1 and its recently synthesized phosphopeptide analog V2p in rodents using a range of methods. The studied peptides significantly reduced acute (mean V1–9.0, V2p–5.8 vs. controls–54.1 s) and inflammatory (mean V1–57.9 and V2p–53.3 vs. controls–107.6 s) nociceptive pain in the formalin test, as well as carrageenan-induced hyperalgesia (mean V1–184.7 and V2p–107.3 vs. controls–61.8 g) in the paw pressure test. These effects are mediated by activation of opioid receptors with a predominance of kappa in V1 antinociception and by delta, kappa, and mu receptors in V2p-induced antinociception. Both peptides did not change the levels of TNF-alpha and IL-1-beta in blood serum. V1 induces depression-like behavior, and V2p shows a tendency toward anxiolysis and short-term impairment of motor coordination without affecting exploratory behavior. The results characterize valorphin and its derivative as promising analgesics that exert their effects both centrally and peripherally, without causing severe behavioral changes in experimental animals. These encouraging data are a foundation for future studies focusing on the effects of hemorphins after long-term treatment.

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Section: Discussionmentioning

confidence: 99%

Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents

Todorov,

Assenov,

Angelov

et al. 2023

Biomedicines

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“…Synthetic organophosphorus inhibitors of acetylcholinesterase (AChE) are ubiquitous in many areas of human activity from agriculture: in the form of insecticides [ 1 , 2 ] through medicine: anti-inflammatory drugs and potential treatments of neurological diseases [ 3 , 4 ] to modern warfare: nerve agents [ 5 ]. Despite their potential medical use however, the majority of such applications are related to termination rather than sustaining life: the acute toxicity and lethality of these compounds is caused by their ability to irreversible impair the enzymatic ability to operate.…”

Section: Introductionmentioning

confidence: 99%

Novichok Nerve Agents as Inhibitors of Acetylcholinesterase—In Silico Study of Their Non-Covalent Binding Affinity

Madaj,

Gostyński,

Chworos

et al. 2024

Molecules

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In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized–Born surface area (MM/GBSA) were applied to assess quantitatively differences between the binding energies of acetylcholine (ACh; the natural agonist of AChE) and neurotoxic, synthetic correlatives (so-called “Novichoks”, and selected compounds from the G- and V-series). Several additional quantitative descriptors like root-mean-square fluctuation (RMSF) and the solvent accessible surface area (SASA) were briefly discussed to give—to the best of our knowledge—the first quantitative in silico description of AChE—Novichok non-covalent binding process and thus facilitate the search for an efficient and effective treatment for Novichok intoxication and in a broader sense—intoxication with other warfare nerve agents as well.

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“…Aminophosphonates structurally and functionally mimic the amino acids. The tetrahedral phosphonic acid is an effective surrogate of the planar carboxylic group, making them attractive targets for the development of biologically active compounds [32,33,[46][47][48][49][50][51][52].…”

Section: Introductionmentioning

confidence: 99%

Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies

et al. 2023

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The efficient one-pot halofluorination of a β-enaminophosphonate/β-iminophosphonate tautomeric mixture resulting in α,α-halofluorinated β-iminophosphonates is reported. Subsequent imine reduction gave the corresponding β-aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of N-inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the cis/trans geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of cis/trans-fluoroaziridine mixture 24, allows us to isolate chiral trans-aziridines 24 as well as cis-aziridines 27 that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the SN2 intramolecular cyclization of vicinal haloamines have been modeled.

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Synthesis and Biological Studies of Novel Aminophosphonates and Their Metal Carbonyl Complexes (Fe, Ru)

Cited by 5 publications

References 51 publications

Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents

Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents

Novichok Nerve Agents as Inhibitors of Acetylcholinesterase—In Silico Study of Their Non-Covalent Binding Affinity

Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies

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