title: Conformational analysis of a 4-hydroxyequilenin Guanine adduct using density functional theory.
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 approximately 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.
authors.affiliation: Department of Chemistry, New York University, 1001 Main Building, 31 Washington Place, New York 10003, USA.
authors.forename: Shixiang
authors.initials: S
authors.lastname: Yan
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Shuang
authors.initials: S
authors.lastname: Ding
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
authors.forename: Suse
authors.initials: S
authors.lastname: Broyde
mesh_terms: D004855:Equilenin / Q000031:analogs & derivatives* / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
chemical_list: D006147:Guanine; C065250:4-hydroxy-equilenin; D004855:Equilenin