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-Fong Liu, Edmond J. LaVoie

研究成果: 雜誌貢獻文章

36 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)2818-2824
頁數7
期刊Journal of Medicinal Chemistry
40
發行號18
DOIs
出版狀態已發佈 - 八月 29 1997
對外發佈Yes

ASJC Scopus subject areas

  • Organic Chemistry

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