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

doi:10.1039/C4MD00411F

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

Synthetic and Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

23 Downloads (Pure)

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 language	English
Pages (from-to)	187-191
Number of pages	5
Journal	MedChemComm
Volume	6
Early online date	22 Oct 2014
DOIs	https://doi.org/10.1039/C4MD00411F
Publication status	Published - 2015

Keywords

Prodrug
Azinomycin
Cytochrome P-450 CYP1A1

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10.1039/C4MD00411F

Med chem comm 2014Accepted author manuscript, 944 KB

Mark Searcey
- M.Searceyuea.acuk
- School of Chemistry, Pharmacy and Pharmacology - Pro-Vice-Chancellor
- Synthetic and Medicinal Chemistry - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching and Research

Cite this

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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.",

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pages = "187--191",

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T1 - Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

AU - Vinader, Victoria

AU - Sadiq, Maria

AU - Sutherland, Mark

AU - Huang, Menying

AU - Loadman, Paul

AU - Elsalem, Lina

AU - Shnyder, Steven

AU - Cui, Hongjuan

AU - Afarinkia, Kamyar

AU - Searcey, Mark

AU - Patterson, Laurence

AU - Pors, Klaus

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Prodrug

KW - Azinomycin

KW - Cytochrome P-450 CYP1A1

U2 - 10.1039/C4MD00411F

DO - 10.1039/C4MD00411F

M3 - Article

SN - 2040-2511

VL - 6

SP - 187

EP - 191

JO - MedChemComm

JF - MedChemComm

ER -

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Abstract

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Mark Searcey

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