2'-Substituted 5-phenylterbenzimidazoles as topoisomerase I poisons

Meera Rangarajan, Jung Sun Kim, Song Jin, Sai Peng Sim, Angela Liu, Daniel S. Pilch, Leroy F. Liu, Edmond J. Lavoie

研究成果: 雜誌貢獻文章同行評審

14 引文 斯高帕斯(Scopus)


5-Phenylterbenzimidazole (1) is active as a topoisomerase I poison (topo I) and is cytotoxic to human tumor cells. No cross-resistance was observed for 1 when it was evaluated against the camptothecin-resistant cell line, CPT-K5. Derivatives of 1 substituted at the 2'-position, however, did exhibit cross-resistance to this cell line. The basis for the resistance of this cell line towards CPT is that it possesses a mutant form of topo I. These results suggest that substituents at the 2'-position may be in proximity to the wild-type enzyme. Therefore, we hypothesized that terbenzimidazoles with 2'-substituents could be capable of interacting with the enzyme and thereby influence activity within this class of topo I poisons. 5-Phenylterbenzimidazoles with a hydroxy, hydroxymethyl, mercapto, amino, N-benzoylaminomethyl, chloro, and trifluoromethyl group at the 2'-position were synthesized. In addition, several 2'-ethyl-5-phenylterbenzimidazoles were prepared containing either a methoxy, hydroxy, amino, or N-acetylamino group at the 2-position of the ethyl side-chain. These 2'-substituted 5-phenylterbenzimidazoles were evaluated as topo I poisons and for cytotoxic activity. The presence of a strong electron-withdrawing group at the 2'-position, such as a chloro or trifluoromethyl group, did enhance both topo I poisoning activity and cytotoxicity. Studies on the relative DNA binding affinity of 1 to its 2'-amino and 2'-trifluoromethyl derivatives did exhibit a correlation with their relative differences in biological activity. Copyright (C) 2000 Elsevier Science Ltd.

頁(從 - 到)1371-1382
期刊Bioorganic and Medicinal Chemistry
出版狀態已發佈 - 6月 2000

ASJC Scopus subject areas

  • 生物化學
  • 分子醫學
  • 分子生物學
  • 藥學科學
  • 藥物發現
  • 臨床生物化學
  • 有機化學


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