title: Preparation of oligodeoxynucleotides containing a diastereoisomer of alpha-(N(2)-2'-deoxyguanosinyl)tamoxifen by phosphoramidite chemical synthesis.
abstract: Women treated with an antiestrogen tamoxifen (TAM) for endocrine therapy or prevention of breast cancer show an increased risk of developing endometrial cancer. TAM-DNA adducts have been detected in the liver of rodents treated with TAM and in the endometrium of women taking TAM. The major TAM adducts have been identified as diastereoisomers of trans- and cis-forms of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG-N(2)-TAM) and alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen. In the study presented here, we prepared oligodeoxynucleotides containing a diastereoisomer of dG-N(2)-TAM by phosphoramidite chemical synthesis. Initially, the trans- and cis-forms of alpha-aminotamoxifen (alpha-NH(2)-TAM) were synthesized from alpha-hydroxytamoxifen using the Mitsunobu reaction followed by hydrolysis. Thereafter by coupling the trans- and cis-form of alpha-NH(2)-TAM with the DMT-derivative of 2-fluoro-(O(6)-2-(trimethylsilyl)ethyl)-2'-deoxyinosine, the trans- and cis-forms of DMT-dG-N(2)-TAM, respectively, were prepared in high yield and used in the preparation of the phosphoramidite precursors. Large quantities of oligodeoxynucleotides containing a trans- or a cis-form of dG-N(2)-TAM were prepared efficiently by automated DNA synthesizer. The incorporation of dG-N(2)-TAM adduct into the oligodeoxynucleotides was confirmed using (32)P-postlabeling/polyacrylamide gel electrophoresis analysis. These site-specifically modified oligodeoxynucleotides will be used for exploring biological properties and three-dimensional structure of TAM-DNA adducts.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA.
authors.forename: Y R
authors.initials: YR
authors.lastname: Santosh Laxmi
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Lakkaraju
authors.initials: L
authors.lastname: Dasaradhi
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D018736:DNA Adducts / Q000138:chemical synthesis*; D004965:Estrogen Antagonists / Q000737:chemistry*; D007536:Isomerism; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D018736:DNA Adducts; D004965:Estrogen Antagonists; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; C105083:alpha-(N(2)-deoxyguanosinyl)tamoxifen; C434331:phosphoramidite; D013629:Tamoxifen