title: Inhibition of human DNA topoisomerase IIα by two novel ellipticine derivatives.
abstract: Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is an antineoplastic agent that intercalates into DNA and alters topoisomerase II activity. Unfortunately, this compound displays a number of adverse properties. Therefore, to investigate new ellipticine-based compounds for their potential as topoisomerase II-targeted drugs, we synthesized two novel derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2). As determined by DNA decatenation and cleavage assays, ET-1 and ET-2 act as catalytic inhibitors of human topoisomerase IIα and are both more potent than the parent compound. Neither compound impairs the ability of the type II enzyme to bind its DNA substrate. Finally, the potency of ET-1 and ET-2 as catalytic inhibitors of topoisomerase IIα appears to be related to their ability to intercalate into the double helix.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kendra R
authors.initials: KR
authors.lastname: Vann
authors.affiliation: Department of Chemistry, Faculty of Science, Dokuz Eylul University, 35160 Izmir, Turkey.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ergün
authors.affiliation: Department of Medical Biology, Faculty of Medicine, Pamukkale University, 20070 Denizli, Turkey.
authors.forename: Sevil
authors.initials: S
authors.lastname: Zencir
authors.affiliation: Department of Chemistry, Faculty of Science, Dokuz Eylul University, 35160 Izmir, Turkey.
authors.forename: Serkan
authors.initials: S
authors.lastname: Oncuoglu
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232, USA; VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: neil.osheroff@vanderbilt.edu.
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.affiliation: Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, 35100 Izmir, Turkey. Electronic address: zeki.topcu@ege.edu.tr.
authors.forename: Zeki
authors.initials: Z
authors.lastname: Topcu
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004611:Ellipticines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D008745:Methylation; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004611:Ellipticines; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: Anticancer drugs; Catalytic inhibitor; DNA cleavage; DNA intercalation; DNA topoisomerase IIα; Ellipticine derivatives