TERBENZIMIDAZOLES - INFLUENCE OF 2''-SUBSTITUENT, 4-SUBSTITUENT, AND 5-SUBSTITUENT ON CYTOTOXICITY AND RELATIVE POTENCY AS TOPOISOMERASE-I POISONS

Terbenzimidazoles poison the nuclear enzyme topoisomerase I and posses s significant cytotoxic activity against several human tumor cell line s. The relative pharmacological activity of 4,5- and 5,6-benzoterbenzi midazoles was compared to that of 5-phenylterbenzimidazole (3). 5,6-Be nzoterbenzimidazole is inactive as a topoisomerase I poison and did no t exhibit significant cytotoxic activity. In contrast, 4,5-benzoterben zimidazole retained activity as a topoisomerase I poison but exhibited weak cytotoxic activity relative to 3. While 5-(1-naphthyl)terbenzimi dazole is less potent than 3 as a topoisomerase I poison and cytotoxic agent, 5-(2-naphthyl)terbenzimidazole has comparable activity to 3. T he presence of a p-methoxy or p-chloro substituent on the phenyl moiet y did not dramatically alter the pharmacological activity of 3. Severa l analogs of 3 were synthesized wherein the 2''-substituent varied fro m methyl, ethyl, propyl, isopropyl, phenyl to p-methoxyphenyl, Evaluat ion of the intrinsic activity of these analogs as topoisomerase I pois ons indicates that topoisomerase I poisoning was not diminished by the presence of a methyl, ethyl, propyl, and isopropyl substituent at the 2''-position. Among the various 2''-substituted analogs evaluated, on ly in the case of 2''-(p-methoxyphenyl)-5-phenylterbenzimidazole was a significant decrease in cytotoxicity observed.