2′,3′-Dideoxynucleoside 5′-β,γ-(Difluoromethylene) Triphosphates With α-P-Thio or α-P-Seleno Modifications: Synthesis and Their Inhibition of HIV-1 Reverse Transcriptase
| Autor: | Nicholas A. Boyle, Jennifer L. Brooks, Patrick Fagan, John S. Lambert, Marija Prhavc, P. Dan Cook |
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| Rok vydání: | 2005 |
| Předmět: |
Anti-HIV Agents
Chemistry Stereochemistry 2'3' dideoxynucleoside Thio Biological activity General Medicine Sulfides Prodrug Biochemistry Dideoxynucleosides HIV Reverse Transcriptase Nucleoside-diphosphate kinase Phosphorylation cascade Nucleoside Reverse Transcriptase Inhibitor chemistry.chemical_compound Organoselenium Compounds Genetics Nucleoside triphosphate Reverse Transcriptase Inhibitors Molecular Medicine |
| Zdroj: | Nucleosides, Nucleotides & Nucleic Acids. 24:1651-1664 |
| ISSN: | 1532-2335 1525-7770 |
| Popis: | Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity. |
| Databáze: | OpenAIRE |
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