1,3-dihydroxyacridone derivatives as inhibitors of herpes virus replication

Citation
P. Akanitapichat et al., 1,3-dihydroxyacridone derivatives as inhibitors of herpes virus replication, ANTIVIR RES, 45(2), 2000, pp. 123-134
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Microbiology
Journal title
ANTIVIRAL RESEARCH
ISSN journal
0166-3542 → ACNP
Volume
45
Issue
2
Year of publication
2000
Pages
123 - 134
Database
ISI
SICI code
0166-3542(200002)45:2<123:1DAIOH>2.0.ZU;2-G
Abstract
The nuclear enzyme DNA topoisomerase II is a candidate pharmacological targ et for treating herpes virus infections and the novel catalytic inhibitors, 7-chloro-1,3-dihydroxyacridone (compound 1), and 1,3,7-trihydroxyacridone (2) are potential lead compounds [Bastow, K.F., Itoigawa, M., Furukawa, H., Kashiwada, Y., Bori, I.D., Ballas, L.M., Lee, K.-H., 1994. Antiproliferati ve actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets. Bioorg. Med. Chem. 2, 1403-1411; Vance, J.R., Bastow, K.F., 1999. Inhibition of DNA topoisomerase II catalytic activity by the antiviral agents 7-chloro,1,3-d ihydroxyacridone and 1,3,7-trihydroxyacridone. Biochem. Pharmacol. 58, 703- 708]. In this report, four new 1,3-dihydroxyacridone analogs with functiona l groups at either the 5-, 6- or 8-positions (compounds 3-6) were synthesiz ed. Target compounds, three other analogs including compounds 1 and 2 and t hree anticancer drugs that inhibit DNA topoisomerase II (etoposide, amsacri ne and aclarubicin) were then evaluated as selective inhibitors of herpes s implex virus (HSV) replication in cell culture and as enzyme inhibitors in vitro. Etoposide and amsacrine inhibited HSV but acted non-selectively. In general, the activities of 1,3-dihydroxyacridone derivatives as selective a nti-HSV agents and as enzyme inhibitors varied inversely suggesting that DN A topoisomerase II probably is not the critical antiviral target. The 5-Cl congener (compound 3) was the most selective agent (about 26-fold under a s tringent assay condition) but was not an enzyme inhibitor. Results of explo ratory mechanistic studies with compounds 1 and 3 show that HSV replication was blocked at a stage after DNA and late protein synthesis. The acridone derivatives were also tested against human cytomegalovirus (HCMV) replicati on but none of them were active. (C) 2000 Elsevier Science B.V. All rights reserved.