Crosslinking reactions of 4-amino-6-oxo-2-vinylpyrimidine with guanine derivatives and structural analysis of the adducts

Shuhei Kusano, Shogo Ishiyama, Sik Lok Lam, Tsukasa Mashima, Masato Katahira, Kengo Miyamoto, Misako Aida, Fumi Nagatsugi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

DNA interstrand crosslinks (ICLs) are the primary mechanism for the cytotoxic activity of many clinical anticancer drugs, and numerous strategies for forming ICLs have been developed. One such method is using crosslink-forming oligonucleotides (CFOs). In this study, we designed a 4-amino-6-oxo- 2-vinylpyrimidine (AOVP) derivative with an acyclic spacer to react selectively with guanine. The AOVP CFO exhibited selective crosslinking reactivity with guanine and thymine in DNA, and with guanine in RNA. These crosslinking reactions with guanine were accelerated in the presence of CoCl2, NiCl2 ZnCl2 and MnCl2. In addition, we demonstrated that the AOVP CFO was reactive toward 8-oxoguanine opposite AOVP in the duplex DNA. The structural analysis of each guanine and 8-oxoguanine adduct in the duplex DNA was investigated by high-resolution NMR. The results suggested that AOVP reacts at the N2 amine in guanine and at the N1 or N2 amines in 8-oxoguanine in the duplex DNA. This study demonstrated the first direct determination of the adduct structure in duplex DNA without enzyme digestion.

Original languageEnglish
Pages (from-to)7717-7730
Number of pages14
JournalNucleic acids research
Volume43
Issue number16
DOIs
Publication statusPublished - 2015 Jul 28

ASJC Scopus subject areas

  • Genetics

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