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Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs
- Source :
-
Bioorganic & Medicinal Chemistry . Aug2007, Vol. 15 Issue 16, p5519-5528. 10p. - Publication Year :
- 2007
-
Abstract
- Abstract: Phosphonomethoxy nucleoside analogs of the thymine containing nucleoside reverse transcriptase inhibitors (NRTIs), 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), and 2′,3′-dideoxythymidine (ddT), were synthesized. The anti-HIV activity against wild-type and several major nucleoside-resistant strains of HIV-1 was evaluated together with the inhibition of wild-type HIV reverse transcriptase (RT). Phosphonomethoxy analog of d4T, 8 (d4TP), demonstrated antiviral activity with an EC50 value of 26μM, whereas, phosphonomethoxy analogs of ddT, 7 (ddTP), and AZT, 6 (AZTP), were both inactive at concentrations up to 200μM. Bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs improved the anti-HIV activity of 7 and 8 by >150-fold and 29-fold, respectively, allowing for antiviral resistance to be determined. The K65R RT mutant virus was more resistant to the bisPOC prodrugs of 7 and 8 than bisPOC PMPA (tenofovir DF) 1. However, bisPOC prodrug of 7 demonstrated superior resistance toward the RT virus containing multiple thymidine analog mutations (6TAMs) indicating that new phosphonate nucleoside analogs may be suitable for targeting clinically relevant nucleoside resistant HIV-1 strains. [Copyright &y& Elsevier]
- Subjects :
- *PRODRUGS
*PHOSPHONATES
*PHOSPHONIC acids
*DNA polymerases
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 15
- Issue :
- 16
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25490246
- Full Text :
- https://doi.org/10.1016/j.bmc.2007.05.047