title: 2"-Substituted 5-phenylterbenzimidazoles as topoisomerase I poisons.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway 08854, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rangarajan
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.forename: S P
authors.initials: SP
authors.lastname: Sim
authors.forename: A
authors.initials: A
authors.lastname: Liu
authors.forename: D S
authors.initials: DS
authors.lastname: Pilch
authors.forename: L F
authors.initials: LF
authors.lastname: Liu
authors.forename: E J
authors.initials: EJ
authors.lastname: LaVoie
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013057:Spectrum Analysis; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA