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. 2005 Aug 3;127(30):10510-1.
doi: 10.1021/ja053493m.

DNA interstrand cross-link formation initiated by reaction between singlet oxygen and a modified nucleotide

In Seok Hong  1 , Marc M Greenberg
Affiliations

DNA interstrand cross-link formation initiated by reaction between singlet oxygen and a modified nucleotide

In Seok Hong et al. J Am Chem Soc. .

Abstract

DNA is the target of many anti-cancer therapies. These agents damage the biopolymer by oxidation or by alkylation. Interstrand DNA cross-links are believed to be the source of cytotoxicity of anti-tumor agents, such as mitomycin C, which alkylate the biopolymer. In contrast, deoxyguanosine oxidation is the result of reaction between DNA and singlet oxygen, which is the damaging species produced in photodynamic therapy. We have shown that, upon oxidation by singlet oxygen, an analogue of thymidine (2) rearranges to a methide, which forms DNA-DNA interstrand cross-links. This novel process suggests that 2 may be a useful adjuvant in photodynamic therapy.

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Figures

Figure 1
Figure 1
Formation of DNA interstrand cross-links (3, 10 nM) via UV or Rose Bengal sensitized aerobic photolysis. (A) Autoradiogram comparing ISC’s produced upon UV or Rose Bengal (50 μM) sensitized photolysis. (B) Effect of Rose Bengal concentration on ISC formation (30 min photolysis).
Figure 2
Figure 2
Effect of D2O on the consumption of monomeric 2 (50 μM) upon irradiation of Rose Bengal (10 μM).
Figure 3
Figure 3
1H NMR analysis of the reaction of 2 (50 mM) with NaIO4 (50 mM) in deuterated phosphate buffer (50 mM, pD 7.4). (A) Before NaIO4 addition, (B) 10 min after NaIO4 addition, and (C) 24 h after NaIO4 addition.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
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