title: Unprecedented C-selective interstrand cross-linking through in situ oxidation of furan-modified oligodeoxynucleotides.
abstract: Chemical reagents that form interstrand cross-links have been used for a long time in cancer therapy. They covalently link two strands of DNA, thereby blocking transcription. Cross-link repair enzymes, however, can restore the transcription processes, causing resistance to certain anti-cancer drugs. The mechanism of these cross-link repair processes has not yet been fully revealed. One of the obstacles in this study is the lack of sufficient amounts of well-defined, stable, cross-linked duplexes to study the pathways of cross-link repair enzymes. Our group has developed a cross-link strategy where a furan moiety is incorporated into oligodeoxynucleotides (ODNs). These furan-modified nucleic acids can form interstrand cross-links upon selective furan oxidation with N-bromosuccinimide. We here report on the incorporation of the furan moiety at the 2'-position of a uridine through an amido or ureido linker. The resulting modified ODNs display an unprecedented selectivity for cross-linking toward a cytidine opposite the modified residue, forming one specific cross-linked duplex, which could be isolated in good yield. Furthermore, the structure of the formed cross-linked duplexes could be unambiguously characterized.
authors.affiliation: Laboratory for Organic and Biomimetic Chemistry, University of Ghent, Krijgslaan 281 S4, B-9000 Ghent, Belgium.
authors.forename: Marieke
authors.initials: M
authors.lastname: Op de Beeck
authors.forename: Annemieke
authors.initials: A
authors.lastname: Madder
mesh_terms: D000577:Amides / Q000737:chemistry; D001483:Base Sequence; D003432:Cross-Linking Reagents / Q000737:chemistry*; D005663:Furans / Q000737:chemistry*; D007700:Kinetics; D009693:Nucleic Acid Hybridization; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics; D010084:Oxidation-Reduction; D013379:Substrate Specificity; D014529:Uridine / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000577:Amides; D003432:Cross-Linking Reagents; D005663:Furans; D009838:Oligodeoxyribonucleotides; C039281:furan; D014529:Uridine