Trichloroacetaldehyde modified oligonucleotides.
Some commercial batches of dichloroacetic acid (DCA) contain traces of chloral (trichloroacetaldehyde). Using such DCA to effect detritylation during solid-phase oligonucleotide synthesis results in the formation of a family of process impurities in which the atoms of chloral (Cl3CCHO) are incorporated between the 5'-oxygen and phosphorus atoms of an internucleotide linkage. The structure was elucidated by HPLC with UV and MS detection, digestion of the oligonucleotide, synthesis of model compounds, and 1H and 31P NMR spectroscopy. By understanding the chemistry behind its formation, we are now able to limit levels of this impurity in synthetic oligonucleotides by limiting chloral in DCA.
Gaus
Hans
H
Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, CA 92008, USA.
Olsen
Phil
P
Sooy
Kent Van
KV
Rentel
Claus
C
Turney
Brett
B
Walker
Kathleen L
KL
McArdle
James V
JV
Capaldi
Daniel C
DC
D002697:Chloral Hydrate / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D004340:Drug Contamination; D013058:Mass Spectrometry; D015394:Molecular Structure; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*
D009841:Oligonucleotides; D002697:Chloral Hydrate; C021100:trichloroacetaldehyde