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

School of Pharmacy

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

4 Citations (Scopus)

8 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

Access to Document

10.1039/C4MD00411F

Med chem comm 2014Accepted author manuscript, 944 KB

Mark Searcey
- M.Searceyuea.acuk
- School of Pharmacy - Pro-Vice-Chancellor
- Norwich Institute for Healthy Aging - Member
Person: Research Centre Member, Academic, Teaching & Research

Cite this

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title = "Probing cytochrome P450-mediated activation with a truncated azinomycin analogue",

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 generateexclusively 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.",

keywords = "Prodrug , Azinomycin, Cytochrome P-450 CYP1A1",

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

year = "2015",

doi = "10.1039/C4MD00411F",

language = "English",

volume = "6",

pages = "187--191",

journal = "MedChemComm",

issn = "2040-2503",

publisher = "Royal Society of Chemistry",

}

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue. / Vinader, Victoria; Sadiq, Maria; Sutherland, Mark; Huang, Menying; Loadman, Paul; Elsalem, Lina; Shnyder, Steven ; Cui, Hongjuan; Afarinkia, Kamyar; Searcey, Mark; Patterson, Laurence; Pors, Klaus.

In: MedChemComm, Vol. 6, 2015, p. 187-191.

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

TY - JOUR

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 generateexclusively 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 generateexclusively 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

VL - 6

SP - 187

EP - 191

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

ER -

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

Abstract

Keywords

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Mark Searcey

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