Medicinal Chemistry

(Jacob Rumans) #1

the lip, keratitis of the cornea, and encephalitis. Its analog, Ara-C (9.6, cytarabine), is
primarily an antineoplastic drug, but its 2'-fluoro-5-iodo derivative has also shown good
activity against HSV-1. Another enzyme, thymidylate synthase,is involved in pyrimidine
biosynthesis, and this can be exploited by antimetabolites that are mistaken for true
nucleotide metabolites. The enzyme-mediated incorporation of such antimetabolites
into the viral DNA and RNA will destroy the virus, eliminating its infectious properties.
This is in contrast to the mode of action of the antitumor agent 5-fluorouracil, which is
a suicide substrate of thymidylate kinase and inactivates the enzyme, thereby interrupting
the dTTP supply of the tumor cell.
Idoxuridine (9.7) and trifluridine (9.8) are antiviral agents that are phosphorylated to
their active form in virus-infected cells, and thus show specificity for two reasons: their
higher affinity for the viral enzyme, and the higher phosphorylase levels in viral-
infected than in normal cells. Both compounds have been used locally on lesions of
HSV-1 and HSV-2 (the latter of which causes genital herpes, now reaching epidemic
proportions) with fair success. They are rather toxic if administered parenterally, as are
all moderately selective antimetabolities.


Acyclovir (9.9) shows a unique specificity and lack of toxicity in HSV-1, HSV-2, and
varicella (chickenpox, shingles) viral infections. A guanine derivative, acyclovir lacks
the pentose of similar compounds and is phosphorylated at the alcoholic OH by the viral
thymidylate kinase only. Consequently, it is not activated in uninfected cells; additionally,


552 MEDICINAL CHEMISTRY

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