Determination of absolute configurations of 4-hydroxyequilenin-cytosine and -adenine adducts by optical rotatory dispersion, electronic circular dichroism, density functional theory calculations, and mass spectrometry

Shuang Ding, Yan Wang, Alexander Kolbanovskiy, Alexander Durandin, Judy L. Bolton, Richard B. Van Breemen, Suse Broyde, Nicholas E. Geacintov

Research output: Contribution to journalArticle

Abstract

Estrogen components of some hormone replacement formulations have been implicated in the initiation of breast cancer. Some of these formulations contain equine estrogens such as equilin and equilenin that are metabolized to the genotoxic catechol 4-hydroxyequilenin (4-OHEN). Auto-oxidation generates the o-quinone form that reacts with dC and dA in oligodeoxynucleotides to form unusual stable cyclic bulky adducts, with four different stereoisomers identified for each base adduct. The dC and dA adducts have the same unsaturated bicyclo[3.3.1]nonane type linkage site with identical stereochemical characteristics. Stereochemical effects may play an important part in the biological consequences of the formation of 4-OHEN-DNA adducts, and the assignment of the absolute configurations of the stereoisomeric 4-OHEN-dC and -dA adducts is therefore needed to understand structure - function relationships. We used density functional theory (DFT) to compute the specific optical rotations and electronic circular dichroism (ECD) spectra of the four 4-OHEN-C stereoisomers, and the results were compared with experimentally measured optical rotatory dispersion (ORD) and ECD spectra. The predicted ORD curves for the four stereoisomeric base adducts reproduced the shapes and signs of experimental spectra in the transparent spectral region. The stereochemistry of the C3′ atom was determined by comparison of the calculated and experimental ORD and ECD spectra, and the stereochemistry of C2′ was determined by mass spectrometric methods. Combining the ORD and mass spectrometry data, the absolute configurations of the four 4-OHEN-C and the stereochemically identical -dC adducts have been identified. The molecular architecture of the linkage site at the 4-OHEN-C/A and 4-OHEN-dC/dA is identical, and it is shown that the deoxyribose group does not substantially contribute to the optical activities. The absolute configurations of the 4-OHEN-dA adducts were thus deduced by comparing the experimental ORD with computed ORD values of 4-OHEN-A adducts.

Original languageEnglish (US)
Pages (from-to)1739-1748
Number of pages10
JournalChemical Research in Toxicology
Volume21
Issue number9
DOIs
StatePublished - Sep 2008

Fingerprint

Optical Rotatory Dispersion
Cytosine
Adenine
Circular Dichroism
Density functional theory
Mass spectrometry
Mass Spectrometry
Optical Rotation
Stereochemistry
Stereoisomerism
Equilenin
Equilin
Estrogens
Optical rotation
Deoxyribose
DNA Adducts
Oligodeoxyribonucleotides
Horses
4-hydroxy-equilenin
Hormones

ASJC Scopus subject areas

  • Toxicology

Cite this

Determination of absolute configurations of 4-hydroxyequilenin-cytosine and -adenine adducts by optical rotatory dispersion, electronic circular dichroism, density functional theory calculations, and mass spectrometry. / Ding, Shuang; Wang, Yan; Kolbanovskiy, Alexander; Durandin, Alexander; Bolton, Judy L.; Van Breemen, Richard B.; Broyde, Suse; Geacintov, Nicholas E.

In: Chemical Research in Toxicology, Vol. 21, No. 9, 09.2008, p. 1739-1748.

Research output: Contribution to journalArticle

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abstract = "Estrogen components of some hormone replacement formulations have been implicated in the initiation of breast cancer. Some of these formulations contain equine estrogens such as equilin and equilenin that are metabolized to the genotoxic catechol 4-hydroxyequilenin (4-OHEN). Auto-oxidation generates the o-quinone form that reacts with dC and dA in oligodeoxynucleotides to form unusual stable cyclic bulky adducts, with four different stereoisomers identified for each base adduct. The dC and dA adducts have the same unsaturated bicyclo[3.3.1]nonane type linkage site with identical stereochemical characteristics. Stereochemical effects may play an important part in the biological consequences of the formation of 4-OHEN-DNA adducts, and the assignment of the absolute configurations of the stereoisomeric 4-OHEN-dC and -dA adducts is therefore needed to understand structure - function relationships. We used density functional theory (DFT) to compute the specific optical rotations and electronic circular dichroism (ECD) spectra of the four 4-OHEN-C stereoisomers, and the results were compared with experimentally measured optical rotatory dispersion (ORD) and ECD spectra. The predicted ORD curves for the four stereoisomeric base adducts reproduced the shapes and signs of experimental spectra in the transparent spectral region. The stereochemistry of the C3′ atom was determined by comparison of the calculated and experimental ORD and ECD spectra, and the stereochemistry of C2′ was determined by mass spectrometric methods. Combining the ORD and mass spectrometry data, the absolute configurations of the four 4-OHEN-C and the stereochemically identical -dC adducts have been identified. The molecular architecture of the linkage site at the 4-OHEN-C/A and 4-OHEN-dC/dA is identical, and it is shown that the deoxyribose group does not substantially contribute to the optical activities. The absolute configurations of the 4-OHEN-dA adducts were thus deduced by comparing the experimental ORD with computed ORD values of 4-OHEN-A adducts.",
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T1 - Determination of absolute configurations of 4-hydroxyequilenin-cytosine and -adenine adducts by optical rotatory dispersion, electronic circular dichroism, density functional theory calculations, and mass spectrometry

AU - Ding, Shuang

AU - Wang, Yan

AU - Kolbanovskiy, Alexander

AU - Durandin, Alexander

AU - Bolton, Judy L.

AU - Van Breemen, Richard B.

AU - Broyde, Suse

AU - Geacintov, Nicholas E.

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