title: Novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-ones act as covalent poisons of human topoisomerase IIα.
abstract: A number of topoisomerase II-targeted anticancer drugs, including amsacrine, utilize an acridine or related aromatic core as a scaffold. Therefore, to further explore the potential of acridine-related compounds to act as topoisomerase II poisons, we synthesized a series of novel trifluoromethylated 9-amino-3,4-dihydroacridin-1(2H)-one derivatives and examined their ability to enhance DNA cleavage mediated by human topoisomerase IIα. Derivatives containing a H, Cl, F, and Br at C7 enhanced enzyme-mediated double-stranded DNA cleavage ∼5.5- to 8.5-fold over baseline, but were less potent than amsacrine. The inclusion of an amino group at C9 was critical for activity. The compounds lost their activity against topoisomerase IIα in the presence of a reducing agent, displayed no activity against the catalytic core of topoisomerase IIα, and inhibited DNA cleavage when incubated with the enzyme prior to the addition of DNA. These findings strongly suggest that the compounds act as covalent, rather than interfacial, topoisomerase II poisons.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Infante Lara
authors.affiliation: Department of Chemistry, Tennessee State University, Nashville, TN 37209-1561, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Sledge
authors.affiliation: Department of Chemistry, Tennessee State University, Nashville, TN 37209-1561, USA.
authors.forename: Amine
authors.initials: A
authors.lastname: Laradji
authors.affiliation: Department of Chemistry, Tennessee State University, Nashville, TN 37209-1561, USA. Electronic address: cokoro@tnstate.edu.
authors.forename: Cosmas O
authors.initials: CO
authors.lastname: Okoro
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
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000677:Amsacrine / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D053837:DNA Cleavage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000166:Acridines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004247:DNA; D004250:DNA Topoisomerases, Type II
keywords: Acridin-1(2H)-ones; Anticancer drugs; Covalent poison; DNA cleavage; DNA topoisomerase IIα