title: Preferential formation of (5S,6R)-thymine glycol for oligodeoxyribonucleotide synthesis and analysis of drug binding to thymine glycol-containing DNA.
abstract: We previously reported the chemical synthesis of oligonucleotides containing thymine glycol, a major form of oxidative DNA damage. In the preparation of the phosphoramidite building block, the predominant product of the osmium tetroxide oxidation of protected thymidine was (5R,6S)-thymidine glycol. To obtain the building block of the other isomer, (5S,6R)-thymidine glycol, in an amount sufficient for oligonucleotide synthesis, the Sharpless asymmetric dihydroxylation (AD) reaction was examined. Although the reaction was very slow, (5S,6R)-thymidine glycol was obtained in preference to the (5R,6S) isomer. The ratio of (5S,6R)- and (5R,6S)-thymidine glycols was 2:1, and a trans isomer was also formed. When an ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, was used as a co-solvent, the reaction became faster, and the yield was improved without changing the preference. The phosphoramidite building block of (5S,6R)-thymidine glycol was prepared, and oligonucleotides containing 5S-thymine glycol were synthesized. One of the oligonucleotides was used to analyze the binding of distamycin A to thymine glycol-containing DNA by Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR) measurements. Distamycin A bound to a duplex containing either isomer of thymine glycol within the AATT target site, and its binding was observed even when the thymine glycol was placed opposite cytosine.
authors.affiliation: Division of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Koichiro
authors.initials: K
authors.lastname: Manabe
authors.forename: Shinya
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Shigenori
authors.initials: S
authors.lastname: Iwai
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage; D004214:Distamycins / Q000378:metabolism*; D006900:Hydroxylation; D007093:Imidazoles / Q000737:chemistry; D007536:Isomerism; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013936:Thymidine / Q000737:chemistry; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C412621:1-butyl-3-methylimidazolium hexafluorophosphate; D000900:Anti-Bacterial Agents; D004214:Distamycins; D007093:Imidazoles; D009838:Oligodeoxyribonucleotides; D012997:Solvents; C029389:thymine glycol; C030000:stallimycin; D004247:DNA; D013941:Thymine; D013936:Thymidine