title: Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors.
abstract: As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., Tsukuba, Ibaraki 300-2635, Japan. j-kamata@hhc.eisai.co.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Kamata
authors.forename: Toshimi
authors.initials: T
authors.lastname: Okada
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kotake
authors.forename: Jun
authors.initials: J
authors.lastname: Niijima
authors.forename: Katsuji
authors.initials: K
authors.lastname: Nakamura
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uenaka
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Kappei
authors.initials: K
authors.lastname: Tsukahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasu
authors.forename: Nozomu
authors.initials: N
authors.lastname: Koyanagi
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kitoh
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugumi
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007624:KB Cells; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: C496386:8-acetyl-2-(2-(dimethylamino)ethyl)-1H-pyrimido(5,6,1-jk)carbazole-1,3(2H)-dione; D000166:Acridines; D000970:Antineoplastic Agents; D002227:Carbazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II