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N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress.

Abstract

During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30- to 100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress.

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  • Authors+Show Affiliations

    ,

    Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    ,

    Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31127979

    Citation

    Keynes, Robert G., et al. "N10 -carbonyl-substituted Phenothiazines Inhibiting Lipid Peroxidation and Associated Nitric Oxide Consumption Powerfully Protect Brain Tissue Against Oxidative Stress." Chemical Biology & Drug Design, 2019.
    Keynes RG, Karchevskaya A, Riddall D, et al. N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. Chem Biol Drug Des. 2019.
    Keynes, R. G., Karchevskaya, A., Riddall, D., Griffiths, C. H., Bellamy, T. C., Chan, A. W. E., ... Garthwaite, J. (2019). N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. Chemical Biology & Drug Design, doi:10.1111/cbdd.13572.
    Keynes RG, et al. N10 -carbonyl-substituted Phenothiazines Inhibiting Lipid Peroxidation and Associated Nitric Oxide Consumption Powerfully Protect Brain Tissue Against Oxidative Stress. Chem Biol Drug Des. 2019 May 25; PubMed PMID: 31127979.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. AU - Keynes,Robert G, AU - Karchevskaya,Anastasia, AU - Riddall,Dieter, AU - Griffiths,Charmaine H, AU - Bellamy,Tomas C, AU - Chan,A W Edith, AU - Selwood,David L, AU - Garthwaite,John, Y1 - 2019/05/25/ PY - 2019/02/18/received PY - 2019/05/15/revised PY - 2019/05/21/accepted PY - 2019/5/28/pubmed PY - 2019/5/28/medline PY - 2019/5/26/entrez KW - XED KW - antioxidant KW - ferroptosis KW - lipid peroxidation KW - neurodegeneration KW - nitric oxide KW - phenothiazine JF - Chemical biology & drug design JO - Chem Biol Drug Des N2 - During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30- to 100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/31127979/N10_-carbonyl-substituted_phenothiazines_inhibiting_lipid_peroxidation_and_associated_nitric_oxide_consumption_powerfully_protect_brain_tissue_against_oxidative_stress L2 - https://doi.org/10.1111/cbdd.13572 DB - PRIME DP - Unbound Medicine ER -