DNA damage and interstrand cross-link formation upon irradiation of aryl iodide C-nucleotide analogues.

The 5-halopyrimidine nucleotides damage DNA upon UV-irradiation or exposure to gamma-radiolysis via the formation of the 2'-deoxyuridin-5-yl sigma-radical. The bromo and iodo derivatives of these molecules are useful tools for probing DNA structure and as therapeutically useful radiosensitizing agents. A series of aryl iodide C-nucleotides were incorporated into synthetic oligonucleotides and exposed to UV-irradiation and gamma-radiolysis. The strand damage produced upon irradiation of DNA containing these molecules is consistent with the generation of highly reactive sigma-radicals. Direct stand breaks and alkali-labile lesions are formed at the nucleotide analogue and flanking nucleotides. The distribution of lesion type and location varies depending upon the position of the aryl ring that is iodinated. Unlike 5-halopyrimidine nucleotides, the aryl iodides produce interstrand cross-links in duplex regions of DNA when exposed to gamma-radiolysis or UV-irradiation. Quenching studies suggest that cross-links are produced by gamma-radiolysis via capture of a solvated electron, and subsequent fragmentation to the sigma-radical. These observations suggest that aryl iodide C-nucleotide analogues may be useful as probes for excess electron transfer and radiosensitizing agents.