Structure determination of 4-azido-2-pyrimidinone nucleoside analogs using mass spectrometry.
The nucleoside prodrugs 4-azido-ara-C and 2'-fluoro-2', 3'-dideoxy-4-azido-ara-C and their base-catalyzed reaction products were thoroughly characterized by mass spectrometry. The structures of the base-catalyzed reaction products were determined and confirmed using a combination of high-resolution and tandem mass spectrometry with deuterium exchange. An intra-molecular rearrangement reaction occurred in 4-azido-ara-C at physiological pH leading to the formation of a 2',6-anhydro product. A nucleoside of similar structure, 2'-fluoro-2'3'-dideoxy-4-azido-ara-C was studied to determine if the formation of the 2',6-anhydro ring was due to the presence of the 4-azido group or the arabinose 2'-OH group. The 6-position of 2'-fluoro-2',3'-dideoxy-4-azido-ara-C was found to be unreactive at physiological pH, but could add ammonia under strongly basic conditions (pH 11.0, ammonia solution). Finally, the formation of an intriguing tetrazole ring by the 4-azido moiety was observed.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2352, USA.
P P
PP
Wang
L P
LP
Kotra
C K
CK
Chu
M G
MG
Bartlett
D000970:Antineoplastic Agents / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D003561:Cytarabine / Q000031:analogs & derivatives; D013058:Mass Spectrometry; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry; D011741:Pyrimidine Nucleosides / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry*
D000970:Antineoplastic Agents; D001386:Azides; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; D011744:Pyrimidinones; D003561:Cytarabine