Conformational analysis of a 4-hydroxyequilenin guanine adduct using density functional theory

Shixiang Yan, Min Wu, Shuang Ding, Nicholas E. Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

Equilenin, a component of the drug Premarin (Wyeth), can be metabolized to a quinonoid, 4-hydroxyequilenin (4-OHEN). 4-OHEN can react with 2′-deoxynucleosides to form unusual cyclic adducts, among which 4-hydroxyequilenin-2′-deoxyguanosine (4-OHEN-dG) is the major product under physiological conditions. The structure and stereochemistry of one stereoisomer, 4-OHEN-dG1, has been obtained previously using electrospray mass spectrometry and NMR methods [Shen et al. (1997) J. Am. Chem. Soc. 119, 11126-11127]; however, details of the conformations around the linkage site have not yet been investigated. The objective of this paper was to determine the conformation at the five-membered ring linkage site for this adduct. We have carried out a computational investigation involving high level quantum mechanical geometry optimization using density functional theory (DFT) for the 4-hydroxyequilenin-guanine adduct (4-OHEN-G1). Our results reveal that there are three conformational families which differ in the puckering of the five-membered ring at the linkage site and in the cyclohexene-type A ring conformation. The overall structures of all three families are "V"-shaped; however, two are quite compact while the third is more open. The lowest energy structure contains a half chair-type cyclohexene A ring, while two structures whose energies are ∼3-4 kcal/mol higher are boat-type. Since the Watson-Crick hydrogen bonding edge of the modified guanine is obstructed by the formation of this bulky nonplanar adduct, it likely would reside in a groove of the DNA double helix.

Original languageEnglish (US)
Pages (from-to)648-653
Number of pages6
JournalChemical Research in Toxicology
Volume15
Issue number5
DOIs
StatePublished - 2002

Fingerprint

Guanine
Density functional theory
Conformations
Equilenin
Conjugated (USP) Estrogens
Stereochemistry
Deoxyguanosine
Stereoisomerism
Ships
Boats
Hydrogen Bonding
Mass spectrometry
Mass Spectrometry
Hydrogen bonds
Nuclear magnetic resonance
Geometry
DNA
Pharmaceutical Preparations
4-hydroxy-equilenin
cyclohexene

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Conformational analysis of a 4-hydroxyequilenin guanine adduct using density functional theory. / Yan, Shixiang; Wu, Min; Ding, Shuang; Geacintov, Nicholas E.; Broyde, Suse.

In: Chemical Research in Toxicology, Vol. 15, No. 5, 2002, p. 648-653.

Research output: Contribution to journalArticle

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AB - Equilenin, a component of the drug Premarin (Wyeth), can be metabolized to a quinonoid, 4-hydroxyequilenin (4-OHEN). 4-OHEN can react with 2′-deoxynucleosides to form unusual cyclic adducts, among which 4-hydroxyequilenin-2′-deoxyguanosine (4-OHEN-dG) is the major product under physiological conditions. The structure and stereochemistry of one stereoisomer, 4-OHEN-dG1, has been obtained previously using electrospray mass spectrometry and NMR methods [Shen et al. (1997) J. Am. Chem. Soc. 119, 11126-11127]; however, details of the conformations around the linkage site have not yet been investigated. The objective of this paper was to determine the conformation at the five-membered ring linkage site for this adduct. We have carried out a computational investigation involving high level quantum mechanical geometry optimization using density functional theory (DFT) for the 4-hydroxyequilenin-guanine adduct (4-OHEN-G1). Our results reveal that there are three conformational families which differ in the puckering of the five-membered ring at the linkage site and in the cyclohexene-type A ring conformation. The overall structures of all three families are "V"-shaped; however, two are quite compact while the third is more open. The lowest energy structure contains a half chair-type cyclohexene A ring, while two structures whose energies are ∼3-4 kcal/mol higher are boat-type. Since the Watson-Crick hydrogen bonding edge of the modified guanine is obstructed by the formation of this bulky nonplanar adduct, it likely would reside in a groove of the DNA double helix.

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