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.

journal_name

Bioorg Med Chem

authors

Goodell JR,Madhok AA,Hiasa H,Ferguson DM

doi

10.1016/j.bmc.2006.04.044

subject

Has Abstract

pub_date

2006-08-15 00:00:00

pages

5467-80

issue

16

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(06)00344-0

journal_volume

14

pub_type

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