title: Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]isoquinoline-1,3-diones.
abstract: The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.
authors.affiliation: Departamento de Quimica Orgánica y Farmaceútica, Universidad San Pablo CEU, Madrid, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Braña
authors.forename: J M
authors.initials: JM
authors.lastname: Castellano
authors.forename: D
authors.initials: D
authors.lastname: Perron
authors.forename: C
authors.initials: C
authors.lastname: Maher
authors.forename: D
authors.initials: D
authors.lastname: Conlon
authors.forename: P F
authors.initials: PF
authors.lastname: Bousquet
authors.forename: J
authors.initials: J
authors.lastname: George
authors.forename: X D
authors.initials: XD
authors.lastname: Qian
authors.forename: S P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D015057:1-Naphthylamine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D007546:Isoquinolines; D015057:1-Naphthylamine; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C092297:elinafide