2"-Substituted 5-phenylterbenzimidazoles as topoisomerase I poisons

Bioorg Med Chem. 2000 Jun;8(6):1371-82. doi: 10.1016/s0968-0896(00)00054-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology*
  • Cell Line
  • DNA / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Spectrum Analysis
  • Topoisomerase I Inhibitors*


  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Topoisomerase I Inhibitors
  • DNA