Chiang Yu

Structure-activity relationships of benzimidazoles and related heterocycles as topoisomerase I poisons

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.

Structure activity of topoisomerase i poisons related to hoechst 33342

Abstract A series of bisbenzimidazoles related to Hoechst 33342 were synthesized. Data on the relative activity of these bisbenzimidazoles as topoisomerase I poisons suggest that considerable flexibility exists in the location of the tertiary alkylamine moeity. With the exception of arylamine analogs, cytotoxicity was generally consistent with their relative potency as topoisomerase I poisons.

Antineoplastic activity of benzimidazo[1,2-b]-isoquinolines, indolo[2,3-b]quinolines, and pyridocarbazoles

Substituted pyrido[3,4-b]carbazoles, pyrido[2,3-b]carbazoles, indolo[2,3-b]quinolines, and benzimidazo[1,2-b]-isoquinolines were synthesized and evaluated for biological activity. Several methylated derivatives of these heterocyclic compounds had similar activity to ellipticine as mammalian topoisomerase II inhibitors. Methylated derivatives of these heterocyclic compounds were also highly active in vitro, inhibiting the growth of several human tumor cell lines. These data demonstrate that the antineoplastic activity associated with ellipticine can be retained within a wide variety of analogous heterocyclics.