title: A Dual Topoisomerase Inhibitor of Intense Pro-Apoptotic and Antileukemic Nature for Cancer Treatment.
abstract: Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Meier
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Steinhauer
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstraße 5-13, 81377, Munich, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Koczian
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Plitzko
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Jarolim
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Girreser
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstraße 5-13, 81377, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Braig
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.affiliation: Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, University of Munich, Butenandtstraße 5-13, 81377, Munich, Germany.
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute of the Christian Albrechts University in Kiel, Gutenbergstraße 76, 24118, Kiel, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: C000620830:1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate; D000970:Antineoplastic Agents; D009281:Naphthalenes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
keywords: antitumor agents; apoptosis; heterocycles; ring closure; topoisomerase inhibitors