DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA**

Suresh Pujari; Caitlin C Jokipii Krueger; Christopher Chao; Spencer Hutchins; Alexander K Hurben; Gunnar Boysen; Natalia Tretyakova

doi:10.1002/chem.202103245

DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA**

Suresh Pujari, Caitlin C Jokipii Krueger, Christopher Chao, Spencer Hutchins, Alexander K Hurben, Gunnar Boysen, Natalia Tretyakova

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

2 Scopus citations

Abstract

Metabolic activation of the human carcinogen 1,3-butadiene (BD) by cytochrome 450 monooxygenases gives rise to a genotoxic diepoxide, 1,2,3,4-diepoxybutane (DEB). This reactive electrophile alkylates guanine bases in DNA to produce N7-(2-hydroxy-3,4-epoxy-1-yl)-dG (N7-DE-dG) adducts. Because of the positive charge at the N7 position of the purine heterocycle, N7-DEB-dG adducts are inherently unstable and can undergo spontaneous depurination or base-catalyzed imidazole ring opening to give N⁶-[2-deoxy-D-erythro-pentofuranosyl]-2,6-diamino-3,4-dihydro-4-oxo-5-N-1-(oxiran-2-yl)propan-1-ol-formamidopyrimidine (DEB-FAPy-dG) adducts. Here we report the first synthesis and structural characterization of DEB-FAPy-dG adducts. Authentic standards of DEB-FAPy-dG and its ¹⁵N₃-labeled analogue were used for the development of a quantitative nanoLC-ESI⁺-HRMS/MS method, allowing for adduct detection in DEB-treated calf thymus DNA. DEB-FAPy-dG formation in DNA was dependent on DEB concentration and pH, with higher numbers observed under alkaline conditions.

Original language	English (US)
Article number	e202103245
Journal	Chemistry - A European Journal
Volume	28
Issue number	3
DOIs	https://doi.org/10.1002/chem.202103245
State	Published - Jan 13 2022

Bibliographical note

Funding Information:
We thank Yingchun Zhao for his help with MS analysis and Luke Erber for accurate mass measurements. We also thank Robert Carlson (University of Minnesota) for preparing the graphics for this manuscript. This research is supported by a grant from the National Cancer Institute (R01 CA‐100670).

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© 2021 Wiley-VCH GmbH

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title = "DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA**",

abstract = "Metabolic activation of the human carcinogen 1,3-butadiene (BD) by cytochrome 450 monooxygenases gives rise to a genotoxic diepoxide, 1,2,3,4-diepoxybutane (DEB). This reactive electrophile alkylates guanine bases in DNA to produce N7-(2-hydroxy-3,4-epoxy-1-yl)-dG (N7-DE-dG) adducts. Because of the positive charge at the N7 position of the purine heterocycle, N7-DEB-dG adducts are inherently unstable and can undergo spontaneous depurination or base-catalyzed imidazole ring opening to give N6-[2-deoxy-D-erythro-pentofuranosyl]-2,6-diamino-3,4-dihydro-4-oxo-5-N-1-(oxiran-2-yl)propan-1-ol-formamidopyrimidine (DEB-FAPy-dG) adducts. Here we report the first synthesis and structural characterization of DEB-FAPy-dG adducts. Authentic standards of DEB-FAPy-dG and its 15N3-labeled analogue were used for the development of a quantitative nanoLC-ESI+-HRMS/MS method, allowing for adduct detection in DEB-treated calf thymus DNA. DEB-FAPy-dG formation in DNA was dependent on DEB concentration and pH, with higher numbers observed under alkaline conditions.",

author = "Suresh Pujari and {Jokipii Krueger}, {Caitlin C} and Christopher Chao and Spencer Hutchins and Hurben, {Alexander K} and Gunnar Boysen and Natalia Tretyakova",

note = "Funding Information: We thank Yingchun Zhao for his help with MS analysis and Luke Erber for accurate mass measurements. We also thank Robert Carlson (University of Minnesota) for preparing the graphics for this manuscript. This research is supported by a grant from the National Cancer Institute (R01 CA‐100670). Publisher Copyright: {\textcopyright} 2021 Wiley-VCH GmbH",

year = "2022",

month = jan,

day = "13",

doi = "10.1002/chem.202103245",

language = "English (US)",

volume = "28",

journal = "Chemistry - A European Journal",

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TY - JOUR

T1 - DEB-FAPy-dG Adducts of 1,3-Butadiene

T2 - Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA**

AU - Pujari, Suresh

AU - Jokipii Krueger, Caitlin C

AU - Chao, Christopher

AU - Hutchins, Spencer

AU - Hurben, Alexander K

AU - Boysen, Gunnar

AU - Tretyakova, Natalia

N1 - Funding Information: We thank Yingchun Zhao for his help with MS analysis and Luke Erber for accurate mass measurements. We also thank Robert Carlson (University of Minnesota) for preparing the graphics for this manuscript. This research is supported by a grant from the National Cancer Institute (R01 CA‐100670). Publisher Copyright: © 2021 Wiley-VCH GmbH

PY - 2022/1/13

Y1 - 2022/1/13

N2 - Metabolic activation of the human carcinogen 1,3-butadiene (BD) by cytochrome 450 monooxygenases gives rise to a genotoxic diepoxide, 1,2,3,4-diepoxybutane (DEB). This reactive electrophile alkylates guanine bases in DNA to produce N7-(2-hydroxy-3,4-epoxy-1-yl)-dG (N7-DE-dG) adducts. Because of the positive charge at the N7 position of the purine heterocycle, N7-DEB-dG adducts are inherently unstable and can undergo spontaneous depurination or base-catalyzed imidazole ring opening to give N6-[2-deoxy-D-erythro-pentofuranosyl]-2,6-diamino-3,4-dihydro-4-oxo-5-N-1-(oxiran-2-yl)propan-1-ol-formamidopyrimidine (DEB-FAPy-dG) adducts. Here we report the first synthesis and structural characterization of DEB-FAPy-dG adducts. Authentic standards of DEB-FAPy-dG and its 15N3-labeled analogue were used for the development of a quantitative nanoLC-ESI+-HRMS/MS method, allowing for adduct detection in DEB-treated calf thymus DNA. DEB-FAPy-dG formation in DNA was dependent on DEB concentration and pH, with higher numbers observed under alkaline conditions.

AB - Metabolic activation of the human carcinogen 1,3-butadiene (BD) by cytochrome 450 monooxygenases gives rise to a genotoxic diepoxide, 1,2,3,4-diepoxybutane (DEB). This reactive electrophile alkylates guanine bases in DNA to produce N7-(2-hydroxy-3,4-epoxy-1-yl)-dG (N7-DE-dG) adducts. Because of the positive charge at the N7 position of the purine heterocycle, N7-DEB-dG adducts are inherently unstable and can undergo spontaneous depurination or base-catalyzed imidazole ring opening to give N6-[2-deoxy-D-erythro-pentofuranosyl]-2,6-diamino-3,4-dihydro-4-oxo-5-N-1-(oxiran-2-yl)propan-1-ol-formamidopyrimidine (DEB-FAPy-dG) adducts. Here we report the first synthesis and structural characterization of DEB-FAPy-dG adducts. Authentic standards of DEB-FAPy-dG and its 15N3-labeled analogue were used for the development of a quantitative nanoLC-ESI+-HRMS/MS method, allowing for adduct detection in DEB-treated calf thymus DNA. DEB-FAPy-dG formation in DNA was dependent on DEB concentration and pH, with higher numbers observed under alkaline conditions.

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U2 - 10.1002/chem.202103245

DO - 10.1002/chem.202103245

M3 - Article

C2 - 34767297

AN - SCOPUS:85120399492

SN - 0947-6539

VL - 28

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 3

M1 - e202103245

ER -

DEB-FAPy-dG Adducts of 1,3-Butadiene: Synthesis, Structural Characterization, and Formation in 1,2,3,4-Diepoxybutane Treated DNA**

Abstract

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