title: Formation of modified cytosine residues in the presence of depurinated DNA.
abstract: [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.
authors.affiliation: Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, California 92008, USA.
authors.forename: Claus
authors.initials: C
authors.lastname: Rentel
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Batt
authors.forename: Christine
authors.initials: C
authors.lastname: Kurata
authors.forename: Jay
authors.initials: J
authors.lastname: Oliver
authors.forename: Hans
authors.initials: H
authors.lastname: Gaus
authors.forename: Achim H
authors.initials: AH
authors.lastname: Krotz
authors.forename: James V
authors.initials: JV
authors.lastname: McArdle
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Capaldi
mesh_terms: D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D003596:Cytosine; D004247:DNA / Q000737:chemistry*; D003841:Deoxycytidine / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D011687:Purines; D013816:Thermodynamics; D013873:Thionucleotides / Q000737:chemistry*
chemical_list: C503781:OGX-011; D016376:Oligonucleotides, Antisense; D011687:Purines; D013873:Thionucleotides; D003841:Deoxycytidine; D003596:Cytosine; D004247:DNA