2',3'-Dideoxycytidine (ddCyd) is among the most potent of the antihuman 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.

Zhang, H., Stowe, E., Ahluwalia, G., Baker, D., Hebbler, A., Chisena, C., et al. (1993). CHARACTERIZATION OF 2',3'-DIDEOXYCYTIDINE DIPHOSPHOCHOLINE AND 2',3'-DIDEOXYCYTIDINE DIPHOSPHOETHANOLAMINE - PROMINENT PHOSPHODIESTER METABOLITES OF THE ANTI-HIV NUCLEOSIDE 2',3'-DIDEOXYCYTIDINE. DRUG METABOLISM AND DISPOSITION, 21(4), 738-744.

CHARACTERIZATION OF 2',3'-DIDEOXYCYTIDINE DIPHOSPHOCHOLINE AND 2',3'-DIDEOXYCYTIDINE DIPHOSPHOETHANOLAMINE - PROMINENT PHOSPHODIESTER METABOLITES OF THE ANTI-HIV NUCLEOSIDE 2',3'-DIDEOXYCYTIDINE

PERNO, CARLO FEDERICO;
1993-01-01

Abstract

2',3'-Dideoxycytidine (ddCyd) is among the most potent of the antihuman 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.
1993
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
Con Impact Factor ISI
IMMUNODEFICIENCY VIRUS INVITRO; 2',3'-DIDEOXYNUCLEOSIDES; INFECTIVITY; COMPOUND
Zhang, H., Stowe, E., Ahluwalia, G., Baker, D., Hebbler, A., Chisena, C., et al. (1993). CHARACTERIZATION OF 2',3'-DIDEOXYCYTIDINE DIPHOSPHOCHOLINE AND 2',3'-DIDEOXYCYTIDINE DIPHOSPHOETHANOLAMINE - PROMINENT PHOSPHODIESTER METABOLITES OF THE ANTI-HIV NUCLEOSIDE 2',3'-DIDEOXYCYTIDINE. DRUG METABOLISM AND DISPOSITION, 21(4), 738-744.
Zhang, H; Stowe, E; Ahluwalia, G; Baker, D; Hebbler, A; Chisena, C; Musser, S; Kelley, J; Perno, Cf; Johns, D; Cooney, D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/51546
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