Characterization of 2',3'-dideoxycytidine diphosphocholine and 2',3'-dideoxycytidine diphosphoethanolamine. Prominent phosphodiester metabolites of the anti-HIV nucleoside 2',3'-dideoxycytidine.
2',3'-Dideoxycytidine (ddCyd) is among the most potent of the anti-human immunodeficiency virus (HIV) agents of the dideoxynucleoside class. Its pharmacologically active metabolite 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) is an effective inhibitor of HIV reverse transcriptase and thus of HIV replication. ddCyd differs, however, from other dideoxynucleoside agents such as 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine in its capacity to generate phosphodiester metabolites (i.e. ddCDP choline and ddCDP ethanolamine). We have synthesized and characterized these two diesters, and established their identity with the metabolites formed in ddCyd-treated Molt-4 cells. Toward this end, the biologically generated metabolites have been isolated on a preparative scale and compared with the synthetic compounds mass spectroscopically, chromatographically, and enzymatically (i.e. their relative susceptibility to the catabolic enzymes alkaline phosphatase and venom phosphodiesterase). The concentration reached by each of these two phosphodiesters within cells can, under certain conditions, equal or exceed that of ddCTP, and their half-times of disappearance are long, indicating that they may serve as depot forms of ddCyd. The possible role of these phosphodiesters in contributing to the unusual toxicity of ddCyd is discussed.
Hao
Z
Z
Laboratory of Medicinal Chemistry, National Cancer Institute/National Institutes of Health, Bethesda, MD 20892.
Stowe
E E
EE
Ahluwalia
G
G
Baker
D C
DC
Hebbler
A K
AK
Chisena
C
C
Musser
S M
SM
Kelley
J A
JA
Perno
C F
CF
Johns
D G
DG
D002478:Cells, Cultured; D002794:Choline / Q000378:metabolism; D002854:Chromatography, Paper; D003565:Cytidine Diphosphate / Q000031:analogs & derivatives; D003566:Cytidine Diphosphate Choline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000737:chemistry* / Q000378:metabolism; D054306:Dideoxynucleotides; D019856:Ethanolamine; D004983:Ethanolamines / Q000737:chemistry* / Q000378:metabolism; D006678:HIV / Q000187:drug effects*; D054303:HIV Reverse Transcriptase; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors; D016339:Spectrometry, Mass, Fast Atom Bombardment; D016047:Zalcitabine / Q000378:metabolism* / Q000494:pharmacology
D003845:Deoxycytosine Nucleotides; D054306:Dideoxynucleotides; D004983:Ethanolamines; D018894:Reverse Transcriptase Inhibitors; C083198:2',3'-dideoxycytidine diphosphoethanolamine; C083199:2',3'-dideoxycytidine diphosphocholine; D003566:Cytidine Diphosphate Choline; D019856:Ethanolamine; D003565:Cytidine Diphosphate; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; D002794:Choline