[Chemical reaction: See text] Depurination is an important degradation pathway for antisense phosphorothioate oligonucleotides under conditions of thermal stress. We present evidence showing that depurinated oligonucleotides react with cytosine-containing sequences giving products containing a 6-(2-deoxy-beta-D-erythro-pentofuranosyl)-3-(2-oxopropyl)imidazo[1,2-c]pyrimidin-5(6H)-one residue. Further, we demonstrate that the same product is formed upon treatment of 2'-deoxycytidine with 4-oxo-2-pentenal, the latter being an expected byproduct of serial elimination reactions at apurinic sites. In addition to being important for synthetic oligonucleotides, apurinic site formation in cellular DNA is a common occurrence. Because repair of these sites can result in the production of 4-oxo-2-pentenal, it is interesting to speculate whether 6-(2-deoxy-beta-D-erythro-pentofuranosyl)-3-(2-oxopropyl)imidazo[1,2-c]pyrimidin-5(6H)-one residues can form in vivo.

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Nucleic acids U 0700 Formation of Modified Cytosine Residues in the Presence of Depurinated DNA. -(RENTEL, C.; WANG, X.; BATT, M.; KURATA, C.; OLIVER, J.; GAUS, H.; KROTZ, A. H.; MCARDLE, J. V.; CAPALDI*, D. C.; J. Org. Chem. 70 (2005) 20, 7841-7845; ISIS Pharm., Inc., Carlsbad, CA 92008, USA; Eng.) -Lindner 52-185