Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Victoria Vinader, Maria Sadiq, Mark Sutherland, Menying Huang, Paul Loadman, Lina Elsalem, Steven Shnyder, Hongjuan Cui, Kamyar Afarinkia, Mark Searcey, Laurence Patterson, Klaus Pors

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    Abstract

    A deactivated alkene precursor (IC50 = 81 μM) to the azinomycin epoxide natural product can be bioactivated by several cytochromes P450 (CYP) to generate antiproliferative metabolites with increased potency (IC50 = 1-30 μM) in CHOwt cells. CYP1A1 and 3A4 were shown to generate
    exclusively the unnatural and the natural-configured azinomycin epoxide diastereoisomer respectively, while CYP1B1 produced both epoxides in a 3:1 mixture. The antiproliferative activity is linked to DNA damage as demonstrated using the comet assay.
    Original languageEnglish
    Pages (from-to)187-191
    Number of pages5
    JournalMedChemComm
    Volume6
    Early online date22 Oct 2014
    DOIs
    Publication statusPublished - 2015

    Keywords

    • Prodrug
    • Azinomycin
    • Cytochrome P-450 CYP1A1

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