| Autor: |
Boyle NA; Research Laboratories, Biota, Inc., 2232 Rutherford Road, Carlsbad, California 92008, USA., Rajwanshi VK, Prhavc M, Wang G, Fagan P, Chen F, Ewing GJ, Brooks JL, Hurd T, Leeds JM, Bruice TW, Cook PD |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2005 Apr 07; Vol. 48 (7), pp. 2695-700. |
| DOI: |
10.1021/jm040101y |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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