Pyrimidoquinazoline-based antitumor agents. Design of topoisomerase II to DNA cross-linkers with activity against protein kinases.
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.
Skibo
Edward B
EB
Department of Chemistry and Biochemistry, Arizona State University, Tempe, 85287-1604, USA. ESkibo@ASU.edu
Huang
Xiaofen
X
Martinez
Rogelio
R
Lemus
Robert H
RH
Craigo
William A
WA
Dorr
Robert T
RT
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II