title: The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds.
abstract: Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. In order to find stronger DNA binding and more potent cytotoxic compounds, a series of ester-coupled bisanthrapyrazole derivatives of 7-chloro-2-[2-[(2-hydroxyethyl)methylamino]ethyl]anthra[1,9-cd]pyrazol-6(2H)-one (AP9) were designed and evaluated by molecular docking techniques. Because the anthrapyrazoles are unable to be reductively activated like doxorubicin and other anthracyclines, they should not be cardiotoxic like the anthracyclines. Based on the docking scores of a series of bisanthrapyrazoles with different numbers of methylene linkers (n) that were docked into an X-ray structure of double-stranded DNA, five bisanthrapyrazoles (n=1-5) were selected for synthesis and physical and biological evaluation. The synthesized compounds were evaluated for DNA binding and bisintercalation by measuring the DNA melting temperature increase, for growth inhibitory effects on the human erythroleukemic K562 cell line, and for DNA topoisomerase IIalpha-mediated cleavage of DNA and inhibition of DNA topoisomerase IIalpha decatenation activities. The results suggest that the bisanthrapyrazoles with n=2-5 formed bisintercalation complexes with DNA. In conclusion, a novel group of bisintercalating anthrapyrazole compounds have been designed, synthesized and biologically evaluated as possible anticancer agents.
authors.affiliation: Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, MB, Canada R3T 2N2. B_Hasinoff@UManitoba.ca
authors.forename: Brian B
authors.initials: BB
authors.lastname: Hasinoff
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.forename: Xing
authors.initials: X
authors.lastname: Wu
authors.forename: Lynn J
authors.initials: LJ
authors.lastname: Guziec
authors.forename: Frank S
authors.initials: FS
authors.lastname: Guziec
authors.forename: Kyle
authors.initials: K
authors.lastname: Marshall
authors.forename: Jack C
authors.initials: JC
authors.lastname: Yalowich
mesh_terms: D018943:Anthracyclines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009691:Nucleic Acid Denaturation; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013696:Temperature; D059005:Topoisomerase II Inhibitors
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; C055925:anthrapyrazole; D004250:DNA Topoisomerases, Type II