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Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency.
- Source :
-
Antiviral chemistry & chemotherapy [Antivir Chem Chemother] 1998 Mar; Vol. 9 (2), pp. 109-15. - Publication Year :
- 1998
-
Abstract
- Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5'-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study the amino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding alpha-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.
- Subjects :
- Animals
Anti-HIV Agents chemistry
Anti-HIV Agents metabolism
Cell Line
HIV-1 drug effects
Humans
Hydrolysis
Liver enzymology
Magnetic Resonance Spectroscopy
Microbial Sensitivity Tests
Molecular Structure
Stavudine metabolism
Stavudine pharmacology
Swine
Anti-HIV Agents pharmacology
Esterases metabolism
Organophosphorus Compounds chemistry
Stavudine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0956-3202
- Volume :
- 9
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Antiviral chemistry & chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 9875382
- Full Text :
- https://doi.org/10.1177/095632029800900202