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 S.
AU - Jokipii Krueger, Caitlin C.
AU - Chao, Christopher
AU - Hutchins, Spencer
AU - Hurben, Alexander K.
AU - Boysen, Gunnar
AU - Tretyakova, Natalia
N1 - 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 -