Antiviral nucleotides, synthesis

Ribavirin is a synthetic guanosine analogue that possesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza, RS V, HCV, HIV-1, and various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism of action has not been fully elucidated however, it appears to inhibit the synthesis of viral mRNA through an effect on nucleotide pools. Following absorption, host cell enzymes convert ribavirin to its monophosphate, diphosphate, and triphosphate forms. Ribavirin monophosphate... 

F. Jeannot, C. Mathe, G. Gosselin, Synthesis and antiviral evaluation of 3 -C-trifluor-omethylnucleoside derivatives bearing adenine as base. Nucleosides Nucleotides Nucl. Acids 20 (2001) 755-758. 

Due to the importance of modified nucleosides that are also in the base, the development of new biocatalytic processes appUed to the synthesis of derivatives modified in the base is of great interest Adenosine deaminase (ADA) and adenylate deaminase (AMPDA) are biocatalysts that catalyze the hydrolytic deaminahon of purine nucleosides and nucleotides. Some applications of these deaminases for the preparation and transformation of compounds structurally related to nucleosides with potential antitumor and antiviral activities have been described in the last few years [8]. 

Cidofovir (Figure 24.4) is an antiviral cytidine nucleotide analog with inhibitory activity against HCMV and other herpes viruses. Cidofovir is first converted to an active diphosphate form by cellular enzymes. Antiviral effects of cidofovir are due to inhibition of viral DNA polymerase by the diphosphate metabolite (Neyts and De Clercq, 1994 Plosker and Noble, 1999 Scholar and Pratt, 2000). The diphosphate probably interacts with DNA polymerase either as an alternate substrate (incorporation at the 3 end or within the interior of the DNA chain) or as a competitive inhibitor (with respect to the normal substrate dCTP). Cidofovir inhibits HCMV DNA synthesis at intracellular concentrations 1000-fold lower than are required to inhibit cellular DNA synthesis (Neyts and De Clercq, 1994). For HSV-1 and HSV-2 corresponding concentrations are at least 50-fold lower. 

Marquez, V. E. (1989) Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. Nucleotide Analogues Antiviral Agents, ACS Symposium Series 401, pp. 140-155. 

Marchand, A. Mathe, C., Imbach, J.-L. and Gosselin, G. (2000) Synthesis and antiviral evaluation of unnatural P-L-enantiomers of 3 -(luoro- and 3 -az.ido-2, 3 -didcoxy- guanosine derivatives. Nucleosides, Nucleotides Nucleic Acids, 19, 205-217. 

Liu, M.-C., Luo, M.-Z., Mozdziesz, D. E., et al. (2001) Synthesis of halogen-substituted 3-deazaadenosine and 3-deazagunaosine analogues as potential antitumour/antiviral agents. Nucleosides Nucleotides Nucleic Acids, 20, 1975-2000. 

Cidofovir is an antiviral agent that inhibits viral DNA synthesis by interfering with viral DNA polymerase. It is indicated in the treatment of Cytomegalovirus retinitis in patients with AIDS. Cidofovir (l-[(5)-3-hydroxy-2-(phosphonomethoxy)-propyljcytosine dihydrate) is a cytidine nucleotide analog with inhibitory activity against human herpes, papilloma, polyoma, pox, and adenoviruses. 

Fludarabine is a purine antimetabolite. Fludarabine is a fluorinated nucleotide analog of the antiviral agent vidara-bine. Fludarabine s metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase, and DNA primase, thus inhibiting DNA synthesis. It is indicated in refactory or progressive chronic B-ceU lymphocytic leukemia. 

The antiviral mechanism of action of ribavirin relates to alteration of cellular nucleotide pools and inhibition of viral messenger RNA synthesis. Intracellular phosphorylation to the mono-, di-, and triphosphate derivatives is mediated by host cell enzymes. In both uninfected and RSV-infected cells, the predominant derivative (>80%) is the triphosphate, which has an intracellular t,/2 of elimination of less than 2 hours. 

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