Antitumor Agents. 113. New 4β-Arylamino Derivatives of 4-O-Demethylepipodophyllotoxin and Related Compounds as Potent Inhibitors of Human DNA Topoisomerase II

Zhe Qing Wang, Yao Haur Kuo, Dora Schnur, J. Phillip Bowen, Su Ying Liu, Fu Sheng Han, Jang Yang Chang, Yung Chi Cheng, Kuo Hsiung Lee

Research output: Contribution to journalArticlepeer-review

129 Citations (Scopus)

Abstract

A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4β-N-, 4β-O- or 4β-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA toposoimerase II, a basic unsubstituted 4/3-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H6, OH and COOCH3,OCH3, COCH3, CH2OH, 0CH2O, 0CH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.

Original languageEnglish
Pages (from-to)2660-2666
Number of pages7
JournalJournal of Medicinal Chemistry
Volume33
Issue number9
DOIs
Publication statusPublished - 1990
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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