Terbenzimidazoles: Influence of 2''-, 4-, and 5-substituents on cytotoxicity and relative potency as topoisomerase I poisons

Jung Sun Kim, Chiang Yu, Angela Liu, Leroy F. Liu, Edmond J. LaVoie

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41 Citations (Scopus)


Terbenzimidazoles poison the nuclear enzyme topoisomerase I and possess significant cytotoxic activity against several human tumor cell lines. The relative pharmacological activity of 4,5- and 5,6-benzoterbenzimidazoles was compared to that of 5-phenylterbenzimidazole (3). 5,6-Benzoterbenzimidazole is inactive as a topoisomerase I poison and did not exhibit significant cytotoxic activity. In contrast, 4,5-benzoterbenzimidazole retained activity as a topoisomerase I poison but exhibited weak cytotoxic activity relative to 3. While 5-(1-naphthyl)-terbenzimidazole is less potent than 3 as a topoisomerase I poison and cytotoxic agent, 5-(2-naphthyl)terbenzimidazole has comparable activity to 3. The presence of a p-methoxy or p-chloro substituent on the phenyl moiety did not dramatically alter the pharmacological activity of 3. Several analogs of 3 were synthesized wherein the 2''-substituent varied from methyl, ethyl, propyl, isopropyl, phenyl to p-methoxyphenyl. Evaluation of the intrinsic activity of these analogs as topoisomerase I poisons indicates that topoisomerase I poisoning was not diminished by the presence of a methyl, ethyl, propyl, and isopropyl substituent at the 2''-position. Among the various 2''-substituted analogs evaluated, only in the case of 2''-(p-methoxyphenyl)-5-phenylterbenzimidazole was a significant decrease in cytotoxicity observed.

Original languageEnglish
Pages (from-to)2818-2824
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - Aug 29 1997
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine


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