Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases

Edward B. Skibo, Xiaofen Huang, Rogelio Martinez, Robert H. Lemus, William A. Craigo, Robert T. Dorr

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.

Original languageEnglish (US)
Pages (from-to)5543-5555
Number of pages13
JournalJournal of Medicinal Chemistry
Volume45
Issue number25
DOIs
StatePublished - Dec 5 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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