Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors

被引：37

作者：

Kamata, J ^{[1
]}

Okada, T ^{[1
]}

Kotake, Y ^{[1
]}

Niijima, J ^{[1
]}

Nakamura, K ^{[1
]}

Uenaka, T ^{[1
]}

Yamaguchi, A ^{[1
]}

Tsukahara, K ^{[1
]}

Nagasu, T ^{[1
]}

Koyanagi, N ^{[1
]}

Kitoh, K ^{[1
]}

Yoshimatsu, K ^{[1
]}

Yoshino, H ^{[1
]}

Sugumi, H ^{[1
]}

机构：

[1] Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 3002635, Japan

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2004年 / 52卷 / 09期

关键词：

topoisomerase II inhibitor; cleavable complex; solid tumor; pyrimidocarbazole;

D O I：

10.1248/cpb.52.1071

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC50 values of 0.049 muM and 0.35 muM 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.

引用

页码：1071 / 1081

页数：11

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