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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 and Chemotherapy. 9:109-115
- Publication Year :
- 1998
- Publisher :
- SAGE Publications, 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 theamino 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 α-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.
- Subjects :
- 0301 basic medicine
Magnetic Resonance Spectroscopy
Anti-HIV Agents
Swine
Stereochemistry
030106 microbiology
Microbial Sensitivity Tests
Biology
01 natural sciences
Esterase
Chemical synthesis
Cell Line
03 medical and health sciences
chemistry.chemical_compound
Organophosphorus Compounds
medicine
Animals
Humans
Molecular Structure
Hydrolysis
Stavudine
Esterases
Biological activity
Phosphoramidate
General Medicine
Prodrug
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Liver
chemistry
Dideoxynucleotide
HIV-1
Nucleoside
medicine.drug
Subjects
Details
- ISSN :
- 20402066
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Antiviral Chemistry and Chemotherapy
- Accession number :
- edsair.doi.dedup.....a5ce25ac2a3e76b720ada382a03e66ec