Formation of modified cytosine residues in the presence of depurinated DNA.
[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.
Rentel
Claus
C
Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, California 92008, USA.
Wang
Xiaojing
X
Batt
Michael
M
Kurata
Christine
C
Oliver
Jay
J
Gaus
Hans
H
Krotz
Achim H
AH
McArdle
James V
JV
Capaldi
Daniel C
DC
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*
C503781:OGX-011; D016376:Oligonucleotides, Antisense; D011687:Purines; D013873:Thionucleotides; D003841:Deoxycytidine; D003596:Cytosine; D004247:DNA