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  1. Article ; Online: Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

    Egunlusi, Ayodeji O / Malan, Sarel F / Palchykov, Vitalii A / Joubert, Jacques

    Mini reviews in medicinal chemistry

    2024  

    Abstract: Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the ... ...

    Abstract Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage-gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.
    Language English
    Publishing date 2024-01-24
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2104081-3
    ISSN 1875-5607 ; 1389-5575
    ISSN (online) 1875-5607
    ISSN 1389-5575
    DOI 10.2174/0113895575273868231128104121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5891: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  2. Article ; Online: The formation of the salt and neutral molecule cocrystal from equimolar solution of heliamine and bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid.

    Shishkina, Svitlana V / Isaiev, Ivan A / Urzhuntseva, Viktoriya V / Palchykov, Vitalii A

    Acta crystallographica Section B, Structural science, crystal engineering and materials

    2019  Volume 75, Issue Pt 2, Page(s) 192–200

    Abstract: The possible interaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (heliamine) with bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid anhydride has been studied. Instead of the reaction with heliamine, the acid anhydride was hydrolyzed into the ... ...

    Abstract The possible interaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (heliamine) with bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid anhydride has been studied. Instead of the reaction with heliamine, the acid anhydride was hydrolyzed into the appropriate dicarboxylic acid. An equimolar mixture of unreacted heliamine and in-situ-generated dicarboxylic acid crystallized in space group P2
    Language English
    Publishing date 2019-03-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2020841-8
    ISSN 2052-5206 ; 1600-5740 ; 1600-8650 ; 2052-5192
    ISSN (online) 2052-5206 ; 1600-5740 ; 1600-8650
    ISSN 2052-5192
    DOI 10.1107/S205252061900115X
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Open and rearranged norbornane derived polycyclic cage molecules as potential neuroprotective agents through attenuation of MPP

    Egunlusi, Ayodeji O / Malan, Sarel F / Omoruyi, Sylvester I / Ekpo, Okobi E / Palchykov, Vitalii A / Joubert, Jacques

    European journal of medicinal chemistry

    2020  Volume 204, Page(s) 112617

    Abstract: The neuroprotective effects of closed polycyclic cage molecules such as NGP1-01, memantine and amantadine have been extensively explored. These effects are mostly linked to the antagonism of the N-methyl-d-aspartate (NMDA) receptor- and the blockage of ... ...

    Abstract The neuroprotective effects of closed polycyclic cage molecules such as NGP1-01, memantine and amantadine have been extensively explored. These effects are mostly linked to the antagonism of the N-methyl-d-aspartate (NMDA) receptor- and the blockage of voltage gated calcium channels (VGCC). The synthesis of structurally related open and rearranged cage derivatives has been studied in depth. However, very little is known on their neuroprotective effects. In this study, a series of open and rearranged polycyclic cage molecules containing a norbornane derived scaffold were synthesised and evaluated for cytotoxicity, neuroprotection and calcium blocking effects via the NMDA receptor and VGCC on neuroblastoma cells at a 10 μM concentration. All compounds showed negligible cytotoxicity and were able to significantly attenuate MPP
    MeSH term(s) 1-Methyl-4-phenylpyridinium/pharmacology ; Calcium/metabolism ; Cell Line, Tumor ; Humans ; Ion Transport ; Molecular Docking Simulation ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Norbornanes/chemistry ; Norbornanes/pharmacology ; Polycyclic Compounds/chemistry ; Polycyclic Compounds/pharmacology ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate/metabolism ; Spectrum Analysis/methods ; Structure-Activity Relationship
    Chemical Substances Neuroprotective Agents ; Norbornanes ; Polycyclic Compounds ; Receptors, N-Methyl-D-Aspartate ; 1-Methyl-4-phenylpyridinium (R865A5OY8J) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2020-07-17
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2020.112617
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 784: Show issues Location:
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  4. Article ; Online: Targeting a Cryptic Pocket in a Protein-Protein Contact by Disulfide-Induced Rupture of a Homodimeric Interface.

    Nguyen, Dzung / Xie, Xiulan / Jakobi, Stephan / Terwesten, Felix / Metz, Alexander / Nguyen, T X Phong / Palchykov, Vitalii A / Heine, Andreas / Reuter, Klaus / Klebe, Gerhard

    ACS chemical biology

    2021  Volume 16, Issue 6, Page(s) 1090–1098

    Abstract: Interference with protein-protein interfaces represents an attractive as well as challenging option for therapeutic intervention and drug design. The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, is only functional as a homodimer. ... ...

    Abstract Interference with protein-protein interfaces represents an attractive as well as challenging option for therapeutic intervention and drug design. The enzyme tRNA-guanine transglycosylase, a target to fight Shigellosis, is only functional as a homodimer. Although we previously produced monomeric variants by site-directed mutagenesis, we only crystallized the functional dimer, simply because upon crystallization the local protein concentration increases and favors formation of the dimer interface, which represents an optimal and highly stable packing of the protein in the solid state. Unfortunately, this prevents access to structural information about the interface geometry in its monomeric state and complicates the development of modulators that can interfere with and prevent dimer formation. Here, we report on a cysteine-containing protein variant in which, under oxidizing conditions, a disulfide linkage is formed. This reinforces a novel packing geometry of the enzyme. In this captured quasi-monomeric state, the monomer units arrange in a completely different way and, thus, expose a loop-helix motif, originally embedded into the old interface, now to the surface. The motif adopts a geometry incompatible with the original dimer formation. Via the soaking of fragments into the crystals, we identified several hits accommodating a cryptic binding site next to the loop-helix motif and modulated its structural features. Our study demonstrates the druggability of the interface by breaking up the homodimeric protein using an introduced disulfide cross-link. By rational concepts, we increased the potency of these fragments to a level where we confirmed their binding by NMR to a nondisulfide-linked TGT variant. The idea of intermediately introducing a disulfide linkage may serve as a general concept of how to transform a homodimer interface into a quasi-monomeric state and give access to essential structural and design information.
    MeSH term(s) Binding Sites/drug effects ; Disulfides/chemistry ; Ligands ; Models, Molecular ; Pentosyltransferases/chemistry ; Protein Multimerization/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Zymomonas/chemistry ; Zymomonas/enzymology
    Chemical Substances Disulfides ; Ligands ; Small Molecule Libraries ; Pentosyltransferases (EC 2.4.2.-) ; queuine tRNA-ribosyltransferase (EC 2.4.2.29)
    Language English
    Publishing date 2021-06-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.1c00296
    Database MEDical Literature Analysis and Retrieval System OnLINE

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