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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