Meier C, Knispel T, Marquez V, De Clercq E, Balzarini J; International Conference on Antiviral Research.
Antiviral Res. 1998 Mar; 37: A63 (abstract no. 83).
Institute of Organic Chemistry, University of Wurzburg, Germany.
Different cycloSal-pro-nucleotides of antivirally active 2',3'-dideoxyadenosine derivatives (ddA, d4A, F-beta- (up-) and F-alpha- (down-) ddA) were prepared, chemically hydrolyzed in phosphate buffer at pH 7.3 and in RPMI culture medium containing 10% heat-inactivated fetal calf serum as well as evaluated for their biological activity against HIV-1 and HIV-2. It was shown in chemical hydrolysis studies that these compounds released the monophosphates (ddAMP, d4AMP, 2'-F-ara- and 2'-F-ribo-ddAMP) as the sole nucleoside containing product. Consequently, these phosphotriesters potentially can also act as nucleotide prodrugs in biological systems and thus, circumventing the deamination of the parent nucleoside to the corresponding inosine derivatives by adenosine deaminase (ADA-bypass). The kinetics of the chemical hydrolysis showed a clear relation of the hydrolysis rate and the electronic properties of the aryl-substituent. The mechanism of the chemical hydroysis of the CycloSal-derivatives involves a controlled tandem-reaction. Studies concerning the resistance against deamination to give the inosine derivatives by ADA showed marked enhanced stability of the pro-nucleotides. Additionally, these new compounds were tested in-vitro against HIV-1 and HIV-2 in CEM/O cells compared to the corresponding exhibited significant antiviral activity in evaluation.
Publication Types:
Keywords:
- 2',3'-dideoxy-2',3'-didehydroadenosine monophosphate
- 2',3'-dideoxyadenosine 5'-phosphate
- Adenosine Deaminase
- Adenosine Monophosphate
- Antiviral Agents
- Deoxyadenine Nucleotides
- Dideoxyadenosine
- HIV-1
- HIV-2
- Nucleosides
- Nucleotides
- Prodrugs
- Research
Other ID:
UI: 102236607
From Meeting Abstracts