Topoisomerase I inhibition and cytotoxicity of 5-bromo- and 5-phenylterbenzimidazoles

Topoisomerase I is an enzyme that is essential for maintaining the three-di mensional structure of DNA during the processes of transcription, translati on and mitosis. With the introduction of new clinical agents that are effec tive in poisoning topoisomerase I, this enzyme has proved to be an attracti ve molecular target in the development of anticancer drugs. Several terbenz imidazoles have been identified as potent topoisomerase I poisons. Structur e-activity data on various terbenzimidazoles have revealed that the presenc e of lipophilic substituents at the 5-position of various terbenzimidazoles correlates with enhanced cytotoxicity. While the effect of having substitu ents at both the 5- and 6-positions had not been evaluated, previous studie s did indicate that the presence of a fused benzo-ring at the 5,6-position results in a significant decrease in topoisomerase I poisoning activity and cytotoxicity. In the present study we investigated whether substituents at both the 5- and 6-positions of Varied terbenzimidazoles would allow for re tention of topo I poisoning activity. The 6-bromo, 6-methoxy, or 6-phenyl d erivatives of both 5-bromo- and 5-phenylterbenzimidazole were synthesized a nd evaluated for topo I poisoning activity, as well as their cytotoxicity t oward human lymphoblastoma cells. The data indicate that such derivatives d o retain similar topo I poisoning activity and possess cytotoxicity equival ent to either 5-bromo- or 5-phenylterbenzimidazole. Significant enhancement in the topoisomerase I poisoning activity and cytotoxicity of 5-phenylterb enzimidazole is observed when the 2''-position is substituted with either a chloro or trifluoromethyl substituent. The influence of such substituents on the biological activity of 5, 6-dibromoterbenzimidazole (6a) was also ex plored. In the case of either 2"-chloro-5,6-dibromoterbenzimidazole (6b) or 2"-trifluoromethyl-5,6-dibromoterbenzimidazole (6c), topoisomerase I poiso ning was not enhanced relative to 6a. While cytotoxicity toward RPMI 8402 w as also not significantly affected, comparative studies performed against s everal solid human tumor cell lines did reveal a significant increase in cy totoxicity observed for 6c as compared to 6a. (C) 2000 Elsevier Science Ltd . All rights reserved.