Issue 1, 2015
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MedChemComm

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. Pattersona  and  Klaus Pors*a  

* 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.

Graphical abstract: Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

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Article information

DOI
https://doi.org/10.1039/C4MD00411F
Article type
Concise Article
Submitted
15 Sep 2014
Accepted
14 Oct 2014
First published
22 Oct 2014

Med. Chem. Commun., 2015,6, 187-191

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Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

V. Vinader, M. Sadiq, M. Sutherland, M. Huang, P. M. Loadman, L. Elsalem, S. D. Shnyder, H. Cui, K. Afarinkia, M. Searcey, L. H. Patterson and K. Pors, Med. Chem. Commun., 2015, 6, 187 DOI: 10.1039/C4MD00411F

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