Synthesis of oligodeoxynucleotides containing a single 6alpha- or 6beta-diastereoisomer of N2-(estradiol-6-yl)-2'-deoxyguanosine.
DNA damage induced by estrogens is associated with developing breast, ovary, and endometrial cancers. The quinone of 2-hydroxyestrogen (2-OHE), a major estrogen metabolite, produces 2-OHE-derived dG and dA adducts in DNA. N(2)-[Estradiol-6(alpha or beta)-yl]-2'-deoxyguanosine [dG-N(2)-6(alpha or beta)-E(2)] lacking a 2-OH moiety may also be formed through sulfonation of 6-hydroxyestrogen. To explore the biological properties of such estrogen-DNA adducts, oligodeoxynucleotides modified by estrogen-derived DNA adduct were prepared by chemical synthesis. Initially, 6alpha- and 6beta-aminoestradiol 17-acetate (6alpha- and 6beta-NH(2)-E(2) 17Ac) were prepared by reductive amination of 6-oxo-estradiol 3,17-diacetate. The DMT-phosphoramidite derivative of N(2)-(3,17-diacetoxyestradiol-6alpha-yl)-2'-deoxyguanosine and its 6beta-isomer were prepared by coupling 5'-O-(4,4'-dimethoxytrityl)-2-fluoro-O(6)-[2-(4-nitrophenyl)ethyl]-2'-deoxyinosine separately with 6alpha- and 6beta-forms of NH(2)-E(2) 17Ac, respectively, followed by selective acetylation of the steroidal 3-hydroxyl group. The desired oligodeoxynucleotide containing a single dG-N(2)-6alpha-E(2) or dG-N(2)-6beta-E(2) was prepared efficiently by an automated DNA synthesizer. Synthesis of these site-specifically modified oligodeoxynucleotides will benefit further research into the biological properties and three-dimensional structure of 6alpha- and 6beta-diastereoisomers of estrogen-DNA adducts.
Itoh
Shinji
S
Hokkaido Pharmaceutical University School of Pharmacy, 7-1, Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan. itoh-m33@hokuyakudai.ac.jp
Shibutani
Shinya
S
Ikegami
Masazumi
M
Watanabe
Shingo
S
Laxmi
Y R Santosh
YR
Suzuki
Naomi
N
Kohda
Kohfuku
K
Takanashi
Kaori
K
Yoshizawa
Itsuo
I
D002851:Chromatography, High Pressure Liquid; D004260:DNA Repair; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009153:Mutagens / Q000138:chemical synthesis*; D009841:Oligonucleotides / Q000138:chemical synthesis*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D007202:Indicators and Reagents; D009153:Mutagens; C510954:N(2)-(estradiol-6-yl)-2'-deoxyguanosine; D009841:Oligonucleotides; D006151:Guanosine; D004958:Estradiol