Antiviral agents, preparation

Biomedical Uses. The molybdate ion is added to total parenteral nutrition protocols and appears to alleviate toxicity of some of the amino acid components in these preparations (see Mineral NUTRIENTS) (97). Molybdenum supplements have been shown to reduce iiitrosarnine-induced mammary carcinomas in rats (50). A number of studies have shown that certain heteropolymolybdates (98) and organometaUic molybdenum compounds (99) have antiviral, including anti-AIDS, and antitumor activity (see Antiviral agents Chemotherapeutics, anticancer). 

Neopentanoyl chloride has been used in the preparation of AZT (56), which is used in the treatment of acquired immune deficiency syndrome (AIDS) (see Antiviral agents). 

Compounds prepared from naturally occurring nucleosides are of course more closely related to genetic material and may have a better chance of interacting with infected cells. Mercu-ration of the 2 -dcoxyuridine 113 leads to the organometallic derivative 114 reaction of that with ethylene in the presence dilithio palladium tetrachloride gives the alkylation product 115 this is reduced catalytically in situ. There is thus obtained the antiviral agent edoxudine (116) [25]. 

The Suzuki coupling of 44 was utilized to prepare 5-substituted uracils as potential antiviral agents [21, 22]. Adduct 45, derived from 44 and 2-bromo-3-methylthiophene, was transformed to the corresponding uracil 46 via acidic hydrolysis. Conveniently, reversal of the coupling partners also resulted in formation of adduct 45, assembled from the Suzuki coupling of 5-bromo-2,4-di-f-butoxypyrimidine (43) and 3-methyl-2-thiopheneboronic acid. 

In an attempt to obtain prodrugs of the antiviral agents 2, 3 -didehydro-2, 3 -dideoxyadenosine (9.33, Base = adeninyl) and 2, 3 -didehydro-2, 3 -dideoxycytosine (9.33, Base = cytosinyl), a variety of phosphorylated derivatives were prepared and tested [91]. Whereas phosphonates (9.31, R = Me or Ph) were inactive, diesters of structure 9.31 (R = MeO or PhO, Base =... 

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... 

Figure 17.32 An early warning system. Virally infected cells release interferons to warn neighbouring cells to prepare for a viral attack. Discovery of these antiviral agents in the 1950s led to great expectations for cures for many diseases. Sadly, it never came to pass.

Among a number of other homochiral furanosyl- and isoxazolidinylthymine targets, these workers also applied an achiral cycloaddition approach with vinyl acetate to successfully prepare the antiviral agent d4T (11) and its 2-methyl analogue (Fig. 1.1) (45). In more recent work, similar nitrones [9, R = Me or benzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues. 

Other examples of spirocyclic 2-amino-4(5//)-oxazolones have been prepared and evaluated for their CNS activity and as potential antiviral agents. " In these reports, cyclization of the appropriate ot-hydroxy ester with guanidine afforded the novel analogues 93, albeit in low-to-modest yields. Representative examples are shown in Table 6.4 (Fig. 6.10). 

L.M. von Itzstein, W.Y. Wu, V. Phan Tho, B. Danylec, and B. Jin, Preparation of Derivatives and Analogs of 2-Deoxy-2,3-Didehydro-N-Acetylneuraminic Acid as Antiviral Agents, Biota Scientific Management Pty. Ltd., Australia, 1991, WO 9116320. 

The interesting homochiral diol derivative (-)-259 (Scheme 52) has been prepared and used by Trost and co-workers in the synthesis of the antiviral agents (-)-carbovir [(-)-256] and (-)-aristeromycin [(-)-262] (92JA8745). 

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