Antiviral nucleosides, prodrugs

E. J. Mclntee, R. P. Remmel, R. F. Schinazi, T. W. Abraham, C. R. Wagner, Probing the Mechanism of Action and Decomposition of Amino Acid Phosphomonoester Amidates of Antiviral Nucleoside Prodrugs , J. Med. Chem. 1997, 40, 3323-3331. 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

Perigaud reported the synthesis of the /f-phosphonamidate of AZT (169). It was synthesized by the successive coupling of AZT to bis(diisopropylamino) chlorophosphine and in situ hydrolysis in the presence of tetrazole and water. Phosphorodiamides (170-179) have also been reported as prodrugs for antiviral nucleosides. These were prepared by quenching the reaction between phosphorus oxychloride and the nucleoside with an excess of amine in methanol or dioxane. 

Unfortunately, charged phosphorylated or phosphonylated nucleosides are unable to penetrate the cell membranes or the blood-brain barrier because of their low lipophiUci-ty. Meier et al. [66] have described the synthesis of a new prodrug system for antiviral nucleosides AZT and ddT based on a-hydroxybenzylphosphonates 1, which present uncharged prodrugs of 5 -nucleoside H-phosphonates and 5 -nucleoside monophosphates. All compounds 1 exhibited pronounced activity against HIV-l- and HlV-2-infected cells without toxicity. Compounds 3 can be considerd as potential prodrugs of the 3 -azido-3 -deoxythimidine and 2, 3 -deoxythimidine, their H-phosphonate monoesters as well as their monophosphates. 

Recent advances towards the design of prodrugs of phosphates and phos-phonates are discussed in this review. One such class of therapeutically important compounds are the anti-viral and anti-cancer nucleosides, for example, AZT, ddC, ddl and FdU. For inhibition of HIV, the antiviral nucleosides are successively phosphorylated by host kinases to yield the nucleoside triphosphate which inhibits HIV reverse transcriptase. The first phosphorylation step can be rate-limiting for these nucleosides [7, 8], and therefore there is interest in delivery of the nucleoside monophosphate. Three recent reviews have discussed progress in the area of prodrugs of AZT [9] and nucleotides [10,11 ], and part of this review covers similar material. 

Dideoxyuridine (ddU) is an antiviral agent that proved ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T-cells. This ineffectiveness was ascribed to a lack of substrate affinity of ddU for cellular nucleoside kinases, which prevent it from being metabolized to the active 5 -triphosphate. To overcome this problem, bis[(pivaloyloxy)methyl] 2, 3 -dideoxyuridine 5 -monophosphate (9.41) was prepared and shown to be a membrane-permeable prodrug of 2, 3 -di-deoxyuridine 5 -monophosphate (ddUMP, 9.42) [93]. Indeed, human T-cell lines exposed to 9.41 rapidly formed the mono-, di-, and triphosphate of ddU, and antiviral activity was observed. This example again documents... 

Since the beginning of our work with liposomes that dates back more than 20 years, we chose the approach of the chemical transformation of water-soluble nucleosides of known cytotoxic and antiviral properties into lipophilic drugs or prodrugs (see references summarized in Table 1). 

Shaw has reviewed the various approaches to the synthesis of organophos-phate-oligonucleosides and has further commented on their chemical and biophysical properties along with their interactions with various enzymes such as DNA-polymerases, and compared them to other members of the family of phosphorus modified nucleic acids. She also reported the synthesis of P-tyrosinyl(P-0)-5 -P-nucleosidyl boranophosphates (23a,b), as antiviral and anticancer prodrug candidates. The P-boranophosphates were prepared by reacting a phosphoramidite intermediate obtained from protected tyrosine and the protected nucleoside in the presence of IH-tetrazole, followed by in situ borona-tion of the phosphite triester intermediate. The two diastereomers were then separated by reverse-phase HPLC. ... 

Levatol ) is a (subtype-non-selective) P-adrenoceptor ANTAGONIST. It can be used as an antihypertensive. penbutolol sulfate penbutolol. penciclovir [ban, inn] (Vectavir ) is a synthetic nucleoside analogue antiviral, used topically as a treatment for herpes infections. It can also be used orally in the form of its prodrug famciclovir. It is active as an anti-hiv agent. Pendramine penicillamine. 

Famciclovir is the diacetyl ester prodrug of 6-deoxy penciclovir and lacks intrinsic antiviral activity. Penciclovir (9-[4-hydroxy-3-hydroxymethylbut-l-yl] guanine) is an acyclic guanine nucleoside analog. The side chain differs structurally in that the oxygen has been replaced by a carbon and an additional hydroxymethyl group is present. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Acyclovir is an acyclic guanine nucleoside analog that lacks a 3 -hydroxyl on the side chain. Valacyclovir is the L-valyl ester prodrug of acyclovir. 

Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms. Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes—commonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. 

Antiviral drugs are often antimetabolites that are structural analogs of purine or pyrimidine bases or their nucleoside forms. Many are prodrugs to be activated by host or viral enzymes. The steps in viral replication and the main sites of action of such antiviral drugs are illustrated in Figure V-3-1. 

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