Antitumor agents. 1771. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors
✍ Scribed by Zheng Ji; Hui-Kang Wang; Kenneth F. Bastow; Xiao-Kang Zhu; Sung Jin Cho; Yung-Chi Cheng; Kuo-Hsiung Lee
- Publisher
- Elsevier Science
- Year
- 1997
- Tongue
- English
- Weight
- 239 KB
- Volume
- 7
- Category
- Article
- ISSN
- 0960-894X
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✦ Synopsis
Novel water-soluble 4fl-amino-4'-O-demethylepipodophyllotoxin derivatives (6-12), designed to enhance minor groove binding ability, were synthesized and screened against NCI's in vitro disease-oriented human tumor cells. Among them, 4'-O-demethyl-4fl-[N-(l'"-methyl-4'"-nitro-pyrrole-2'"-carbonyl)-4"-aminoanilino]-4-desoxypodophyllotoxin (10) and its HC1 salt (11) were fomld to exhibit potent cytotoxic activities (average log GIs0 = -6.91, -7.00, and -5.01 for 10, 11, and etoposide, respectively). Compounds 10 and 12 were further tested for their inhibitory activities against DNA topoisomerase II. Compound 10 again exhibited a superior activity profile compared to that of etoposide, displaying increased cytotoxicity against KB and KB-7d cells (IDs0/LD.~0 -0.04/0.15 and 0.2/0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 /~M), and cellular protein DNA complex tbrmation (225%).