title: Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity.
abstract: Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G(1) with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.
authors.affiliation: Laboratory of Molecular Pharmacology, National Cancer Institute, 37 Convent Dr., Bldg. 37, Room 5068, National Institutes of Health, Bethesda, MD 20892-4255, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Keli K
authors.initials: KK
authors.lastname: Agama
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Melinda
authors.initials: M
authors.lastname: Hollingshead
authors.forename: Susan L
authors.initials: SL
authors.lastname: Holbeck
authors.forename: Mollie H
authors.initials: MH
authors.lastname: Wright
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.forename: Muthukaman
authors.initials: M
authors.lastname: Nagarajan
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007192:Indenes / Q000737:chemistry / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007192:Indenes; D007364:Intercalating Agents; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; C513777:bis-1,3-((5,6-dihydro-5,11-diketo-11H-indeno(1,2-c)isoquinoline)-6-propylamino)propane; D004247:DNA; D004250:DNA Topoisomerases, Type II; C039109:isoquinoline; D013936:Thymidine