Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Victoria Vinader; Maria Sadiq; Mark Sutherland; Mengying Huang; Paul M. Loadman; Lina Elsalem; Steven D. Shnyder; Hongjuan Cui; Kamyar Afarinkia; Mark Searcey; Laurence H. Patterson; Klaus Pors

doi:10.1039/C4MD00411F

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue†

Victoria Vinader,^a Maria Sadiq,^a Mark Sutherland,^a Mengying Huang,^b Paul M. Loadman,^a Lina Elsalem,^a Steven D. Shnyder,^a Hongjuan Cui,^b Kamyar Afarinkia,^a Mark Searcey,*^c Laurence H. Patterson^a and Klaus Pors*^a

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* Corresponding authors

^a Institute of Cancer Therapeutics, University of Bradford, West Yorkshire BD7 1DP, UK
E-mail: k.pors1@bradford.ac.uk

^b State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China

^c School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
E-mail: M.Searcey@uea.ac.uk

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.

MedChemComm

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue†

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Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

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