Nucleic Acids in Chemistry and Biology

The inconvenience of the need to administer this drug intravenously for CMV infections can also be over-
come by using the L-valyl ester prodrug, valganciclovir(Figure 3.93) that can be administered orally.
Penciclovir(Figure 3.93) is also used as an anti-herpes drug, particularly for recurrent cold sores and
has the same mechanism of action as the other acyclonucleosides. However, penciclovir has even poorer
oral bioavailability than acyclovir. Fortunately an oral prodrug, famciclovir(Figure 3.93), has been developed,
which is converted into penciclovir through oxidation by xanthine oxidase in the gut, followed by removal
of the acetyl groups by esterases in the liver.

3.7.2.2.2 Nucleotide Analogues. The analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)

adenine (HPMPA)(Figure 3.94), discovered by the groups of Hóly and DeClercq in the 1980s, was the
first nucleotide analogue to show antiviral properties. Deletion of the 5-oxygen creates a phosphonic acid
analogue of a nucleoside 5-phosphate that is stable to nucleotidases. Tenofir disoproxil(Figure 3.94) is a
non-ionic oral prodrug that is converted into its bioactive form (an analogue of HPMPA) following hydroly-
sis in vivo by carboxyl esterases and spontaneous cleavage of the phosphonate esters. It is currently used
in the treatment of HIV. Adefovir dipivoxil(Figure 3.94), a prodrug of PMEA, is used for the treatment of
chronic hepatitis B infections; while the phosphonate derivative cidofovir(Figure 3.94), is licensed for
used in the treatment of HSV infections, and particularly CMV retinitis in AIDS patients. It also shows
activity against a range of other herpes infections and has considerable potential for the treatment of
adeno-, papilloma- and poxvirus infections. In each case, it is necessary for the phosphonic acid to be
accepted as a substrate for a nucleotide kinase to generate the analogues of the 5-diphosphate and 5-
triphosphate sequentially (Figure 3.92).

3.7.2.2.3 5-Substituted-pyrimidine 2
-Deoxyribonucleosides.134–136 5-Iodo-2-deoxyuridine

(Figure 3.95a) was discovered by Prusoff in the 1960s and was the first anti-viral nucleoside to be mar-
keted against HSV and VZV infections as the drug idoxuridine. The mode of action of this nucleoside is
still not known, although it is incorporated into both cellular and viral DNA. It is likely that the toxicity of
this drug arises because both viral and cellular kinases can phosphorylate it and, therefore, it is further
metabolized in infected and non-infected cells.
5-Vinyl-2-deoxyuridine(Figure 3.95b) is in many orders of magnitude more potent than the 5-iodo
derivative against HSV in vitro. While this compound is very toxic in cell culture, in animals it is neither
toxic nor does it have anti-viral properties. This is because the nucleoside is a very good substrate for
nucleoside phosphorylase, an enzyme that is absent from many tissue culture cell lines. The enzyme cleaves
it to give the heterocyclic base and 2-deoxyribose 1-pyrophosphate, neither of which has anti-viral properties.
From this example we learn that nucleoside analogues in this series must be resistant to nucleoside phospho-
rylase in order to possess anti-viral activity. (E)-5-(2-Bromovinyl)-2-deoxyuridine (BVDU; Figure 3.95c)
is even more effective (IC 50 0.001 mg ml^1 ) against HSV-1 and VZV but less so against HSV-2. This is

134 Chapter 3

HO Gua

HO

O

N

N

N

N

NH 2

O

O

O

HO O

Gua

HO

O

H 2 N

O

O

Gua O Gua

HO

O

H 2 N

O

HO

O

Gua

valaciclovir

ganciclovir penciclovir

valganciclovir famciclovir

acyclovir

Figure 3.93 Structures of acyclonucleosides used as anti-viral agents

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