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Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity.

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.
AuthorsJohn R Goodell, Avni A Madhok, Hiroshi Hiasa, David M Ferguson
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 14 Issue 16 Pg. 5467-80 (Aug 15 2006) ISSN: 0968-0896 [Print] England
PMID16713270 (Publication Type: Evaluation Studies, Journal Article)
Chemical References
  • Acridines
  • Antiviral Agents
  • Topoisomerase II Inhibitors
  • Topoisomerase Inhibitors
  • acridone
  • DNA Topoisomerases
  • DNA Topoisomerases, Type II
Topics
  • Acridines (chemical synthesis, pharmacology)
  • 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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