title: Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons.
abstract: A series of substituted 2-(4-methoxyphenyl)-1H-benzimidazoles were synthesized and evaluated as inhibitors of topoisomerase I. The presence of a 5-formyl-, 5-(aminocarbonyl)-, or 5-nitro group (i.e., substituents capable of acting as hydrogen bond acceptors) correlated with the potential of select derivatives to inhibit topoisomerase I. In contrast to bi- and terbenzimidazoles, the substituted benzimidazoles that were active as topoisomerase I poisons exhibited minimum or no DNA binding affinity. 5-Nitro-2-(4-methoxyphenyl)-1H-benzimidazole exhibited the highest activity and was significantly more active than the 4-nitro positional isomer. The 5- and 6-nitro derivatives of 2-(4-methoxyphenyl) benzoxazole, 2-(4-methoxyphenyl)benzothiazole, and 2-(4-methoxyphenyl)indole were synthesized and their relative activity as topoisomerase I inhibitors determined. None of these heterocyclic analogues were effective in significantly inhibiting cleavable-complex formation in the presence of DNA and topoisomerase I, suggesting a high degree of structural specificity associated with the interaction of these substituted benzimidazoles with the enzyme or the enzyme-DNA complex. In evaluating their cytotoxicity, these new topoisomerase I poisons also exhibited no significant cross-resistance against cell lines that express camptothecin-resistant topoisomerase I.
authors: Department of Pharmaceutical Chemistry, Rutgers, State University of New Jersey, Piscataway 08855, USA.
authors: J S
authors: JS
authors: Kim
authors: Q
authors: Q
authors: Sun
authors: B
authors: B
authors: Gatto
authors: C
authors: C
authors: Yu
authors: A
authors: A
authors: Liu
authors: L F
authors: LF
authors: Liu
authors: E J
authors: EJ
authors: LaVoie
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D001583:Benzoxazoles; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin