Synthesis of 2',3'-dideoxynucleoside 5'-alpha-P-borano-beta,gamma-(difluoromethylene)triphosphates and their inhibition of HIV-1 reverse transcriptase
| Autor: | Nicholas A. Boyle, Vivek K. Rajwanshi, Fu Chen, P. Dan Cook, Jennifer L. Brooks, Marija Prhavc, Tiffany Hurd, Patrick Fagan, Guangyi Wang, Janet M. Leeds, Gregory Ewing, Thomas W. Bruice |
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| Rok vydání: | 2005 |
| Předmět: |
Boron Compounds
Stereochemistry Anti-HIV Agents Deoxyribonucleotides In Vitro Techniques Chemical synthesis Zidovudine chemistry.chemical_compound Drug Discovery medicine Animals chemistry.chemical_classification biology Chemistry Stereoisomerism Nucleotidyltransferase Reverse transcriptase HIV Reverse Transcriptase Enzyme Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Reverse Transcriptase Inhibitors Cattle Nucleoside DNA medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 48(7) |
| ISSN: | 0022-2623 |
| Popis: | The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents. |
| Databáze: | OpenAIRE |
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