2'-Substituted 5-phenylterbenzimidazoles as topoisomerase I poisons

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

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14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1371-1382
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number6
DOIs
Publication statusPublished - Jun 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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    Rangarajan, M., Kim, J. S., Jin, S., Sim, S. P., Liu, A., Pilch, D. S., Liu, L-F., & Lavoie, E. J. (2000). 2'-Substituted 5-phenylterbenzimidazoles as topoisomerase I poisons. Bioorganic and Medicinal Chemistry, 8(6), 1371-1382. https://doi.org/10.1016/S0968-0896(00)00054-7