Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors.
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.
Kamata
Junichi
J
Tsukuba Research Laboratories, Eisai Co. Ltd., Tsukuba, Ibaraki 300-2635, Japan. j-kamata@hhc.eisai.co.jp
Okada
Toshimi
T
Kotake
Yoshihiko
Y
Niijima
Jun
J
Nakamura
Katsuji
K
Uenaka
Toshimitsu
T
Yamaguchi
Atsumi
A
Tsukahara
Kappei
K
Nagasu
Takeshi
T
Koyanagi
Nozomu
N
Kitoh
Kyosuke
K
Yoshimatsu
Kentaro
K
Yoshino
Hiroshi
H
Sugumi
Hiroyuki
H
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
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