title: 6H-pyrazolo[4,5,1-de]acridin-6-ones as a novel class of antitumor agents. Synthesis and biological activity.
abstract: The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Limited, Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sugaya
authors.forename: Y
authors.initials: Y
authors.lastname: Mimura
authors.forename: Y
authors.initials: Y
authors.lastname: Shida
authors.forename: Y
authors.initials: Y
authors.lastname: Osawa
authors.forename: I
authors.initials: I
authors.lastname: Matsukuma
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: S
authors.initials: S
authors.lastname: Akinaga
authors.forename: M
authors.initials: M
authors.lastname: Morimoto
authors.forename: T
authors.initials: T
authors.lastname: Ashizawa
authors.forename: M
authors.initials: M
authors.lastname: Okabe
mesh_terms: D000609:Aminoacridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D012510:Sarcoma 180 / Q000188:drug therapy; D014407:Tumor Cells, Cultured
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D011720:Pyrazoles