Biomaterial Database

Topoisomerase I/II inhibition by a novel naphthoquinone containing a modified anthracycline ring system. 2011

Steven Kennedy, and John C DiCesare, and Robert J Sheaff

Department of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK 74104, United States.

In an attempt to create more effective chemotherapeutic compounds, the naphthoquinone adduct 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized. Cell viability studies revealed TU100 is specific for eukaryotes and induces cell death. Based on its structural similarities to the anthracyclines and isoquinolines, the ability of TU100 to inhibit topoisomerase I and II was examined. TU100 was an effective inhibitor of both enzymes, as indicated by its ability to prevent topoisomerase-mediated relaxation of supercoiled plasmid DNA. The mechanism of action does not involve TU100 intercalation into DNA, unlike anthracyclines. Pre-incubation of topoisomerase with TU100 dramatically decreased the IC(50), suggesting the drug is a novel slow acting topoisomerase inhibitor that works in the absence of DNA. Taken together these results indicate the novel naphthoquinone adduct TU100 is a dual topoisomerase I/II inhibitor with a unique mechanism of action and chemotherapeutic potential.

UI	MeSH Term	Description	Entries
D009285	Naphthoquinones	Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups.	Naphthalenediones,Naphthazarins,Naphthoquinone
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D004250	DNA Topoisomerases, Type II	DNA TOPOISOMERASES that catalyze ATP-dependent breakage of both strands of DNA, passage of the unbroken strands through the breaks, and rejoining of the broken strands. These enzymes bring about relaxation of the supercoiled DNA and resolution of a knotted circular DNA duplex.	DNA Topoisomerase (ATP-Hydrolysing),DNA Topoisomerase II,DNA Topoisomerase II alpha,DNA Topoisomerase II beta,DNA Type 2 Topoisomerase,TOP2A Protein,TOP2B Protein,Topoisomerase II,Topoisomerase II alpha,Topoisomerase II beta,Type II DNA Topoisomerase,alpha, Topoisomerase II,beta, Topoisomerase II
D004264	DNA Topoisomerases, Type I	DNA TOPOISOMERASES that catalyze ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break, and rejoining of the broken strand. DNA Topoisomerases, Type I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.	DNA Nicking-Closing Protein,DNA Relaxing Enzyme,DNA Relaxing Protein,DNA Topoisomerase,DNA Topoisomerase I,DNA Topoisomerase III,DNA Topoisomerase III alpha,DNA Topoisomerase III beta,DNA Untwisting Enzyme,DNA Untwisting Protein,TOP3 Topoisomerase,TOP3alpha,TOPO IIIalpha,Topo III,Topoisomerase III,Topoisomerase III beta,Topoisomerase IIIalpha,Topoisomerase IIIbeta,DNA Nicking-Closing Proteins,DNA Relaxing Enzymes,DNA Type 1 Topoisomerase,DNA Untwisting Enzymes,DNA Untwisting Proteins,Topoisomerase I,Type I DNA Topoisomerase,III beta, Topoisomerase,III, DNA Topoisomerase,III, Topo,III, Topoisomerase,IIIalpha, TOPO,IIIalpha, Topoisomerase,IIIbeta, Topoisomerase,Topoisomerase III, DNA,Topoisomerase, TOP3,beta, Topoisomerase III
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D059004	Topoisomerase I Inhibitors	Compounds that inhibit the activity of DNA TOPOISOMERASE I.	DNA Topoisomerase I Inhibitor,DNA Topoisomerase III Inhibitor,DNA Topoisomerase III Inhibitors,DNA Type 1 Topoisomerase Inhibitor,DNA Type III Topoisomerase Inhibitor,DNA Type III Topoisomerase Inhibitors,Topoisomerase 1 Inhibitor,Topoisomerase 1 Inhibitors,Topoisomerase 3 Inhibitor,Topoisomerase 3 Inhibitors,Topoisomerase I Inhibitor,Topoisomerase III Inhibitor,Topoisomerase III Inhibitors,DNA Topoisomerase I Inhibitors,DNA Type 1 Topoisomerase Inhibitors,1 Inhibitor, Topoisomerase,3 Inhibitor, Topoisomerase,3 Inhibitors, Topoisomerase,I Inhibitor, Topoisomerase,III Inhibitor, Topoisomerase,III Inhibitors, Topoisomerase,Inhibitor, Topoisomerase 1,Inhibitor, Topoisomerase 3,Inhibitor, Topoisomerase I,Inhibitor, Topoisomerase III,Inhibitors, Topoisomerase 1,Inhibitors, Topoisomerase 3,Inhibitors, Topoisomerase I,Inhibitors, Topoisomerase III
D059005	Topoisomerase II Inhibitors	Compounds that inhibit the activity of DNA TOPOISOMERASE II. Included in this category are a variety of ANTINEOPLASTIC AGENTS which target the eukaryotic form of topoisomerase II and ANTIBACTERIAL AGENTS which target the prokaryotic form of topoisomerase II.	DNA Gyrase Inhibitor,DNA Topoisomerase II Inhibitor,Topoisomerase 2 Inhibitors,Topoisomerase II Inhibitor,DNA Gyrase Inhibitors,DNA Topoisomerase II Inhibitors,DNA Type 2 Topoisomerase Inhibitors,Gyrase Inhibitor, DNA,Gyrase Inhibitors, DNA,II Inhibitor, Topoisomerase,Inhibitor, DNA Gyrase,Inhibitor, Topoisomerase II,Inhibitors, DNA Gyrase,Inhibitors, Topoisomerase 2,Inhibitors, Topoisomerase II
D041681	NIH 3T3 Cells	A continuous cell line of high contact-inhibition established from NIH Swiss mouse embryo cultures. The cells are useful for DNA transfection and transformation studies. (From ATCC [Internet]. Virginia: American Type Culture Collection; c2002 [cited 2002 Sept 26]. Available from http://www.atcc.org/)	3T3 Cells, NIH,NIH-3T3 Cells,3T3 Cell, NIH,Cell, NIH 3T3,Cell, NIH-3T3,Cells, NIH 3T3,Cells, NIH-3T3,NIH 3T3 Cell,NIH-3T3 Cell