Abstract |
The discovery of new non- nucleoside antiviral compounds is of significant and growing interest for treating herpes virus infections due to the emergence of nucleoside-resistant strains. Using a whole cell virus-induced cytopathogenic assay, we tested a series of substituted triaryl heterocyclic compounds including acridones, xanthones, and acridines. The compounds which showed activity against Herpes Simplex-1 and/or Herpes Simplex-2 were further assayed for inhibition of topoisomerase activity to gain insight into the mechanism of action. The results indicate that the acridine analogs bearing substituted carboxamides and bulky 9-amino functionalities are able to inhibit herpes infections as well as inhibit topoisomerase II relaxation of supercoiled DNA. Given the mechanism of action of amsacrine (a closely related, well-studied 9-amino substituted acridine), the compounds were further tested in a DNA topoisomerase II cleavage assay to determine if the compounds function as poisons. The results show that the acridines synthesized in this study function through a different mechanism to that of amsacrine, most likely by blocking topoisomerase binding to DNA (akin to that of aclarubicin). This not only suggests a unique mechanism of action in treating herpes virus infections, but also may be of great interest in the development of anticancer agents that target topoisomerase II activity.
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Authors | John R Goodell, Avni A Madhok, Hiroshi Hiasa, David M Ferguson |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 14
Issue 16
Pg. 5467-80
(Aug 15 2006)
ISSN: 0968-0896 [Print] England |
PMID | 16713270
(Publication Type: Evaluation Study, Journal Article)
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Chemical References |
- Acridines
- Acridones
- Antiviral Agents
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- acridone
- DNA Topoisomerases
- DNA Topoisomerases, Type II
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Topics |
- Acridines
(chemical synthesis, pharmacology)
- Acridones
- Antiviral Agents
(chemical synthesis, pharmacology)
- DNA Topoisomerases
(metabolism)
- DNA Topoisomerases, Type II
(metabolism)
- Herpesvirus 1, Human
(drug effects, enzymology)
- Herpesvirus 2, Human
(drug effects, enzymology)
- Microbial Sensitivity Tests
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Virus Replication
(drug effects)
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