Rangarajan M, Kim J S, Sim S P, Liu A, Liu L F, Lavoie E J
Department of Pharmaceutical Chemistry, Rutgers, The State University of New Jersey, Piscataway 08854, USA.
Bioorg Med Chem. 2000 Nov;8(11):2591-600. doi: 10.1016/s0968-0896(00)00188-7.
Topoisomerase I is an enzyme that is essential for maintaining the three-dimensional structure of DNA during the processes of transcription, translation and mitosis. With the introduction of new clinical agents that are effective in poisoning topoisomerase I, this enzyme has proved to be an attractive molecular target in the development of anticancer drugs. Several terbenzimidazoles have been identified as potent topoisomerase I poisons. Structure-activity data on various terbenzimidazoles have revealed that the presence of lipophilic substituents at the 5-position of various terbenzimidazoles correlates with enhanced cytotoxicity. While the effect of having substituents at both the 5- and 6-positions had not been evaluated, previous studies 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 retention of topo I poisoning activity. The 6-bromo, 6-methoxy, or 6-phenyl derivatives of both 5-bromo- and 5-phenylterbenzimidazole were synthesized and evaluated for topo I poisoning activity, as well as their cytotoxicity toward human lymphoblastoma cells. The data indicate that such derivatives do retain similar topo I poisoning activity and possess cytotoxicity equivalent to either 5-bromo- or 5-phenylterbenzimidazole. Significant enhancement in the topoisomerase I poisoning activity and cytotoxicity of 5-phenylterbenzimidazole 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 explored. In the case of either 2"-chloro-5,6-dibromoterbenzimidazole (6b) or 2"-trifluoromethyl-5,6-dibromoterbenzimidazole (6c), topoisomerase I poisoning was not enhanced relative to 6a. While cytotoxicity toward RPMI 8402 was also not significantly affected, comparative studies performed against several solid human tumor cell lines did reveal a significant increase in cytotoxicity observed for 6c as compared to 6a.
拓扑异构酶I是一种在转录、翻译和有丝分裂过程中维持DNA三维结构所必需的酶。随着能有效抑制拓扑异构酶I的新型临床药物的出现，这种酶已被证明是抗癌药物开发中一个有吸引力的分子靶点。几种三苯并咪唑已被确定为有效的拓扑异构酶I抑制剂。各种三苯并咪唑的构效关系数据表明，在各种三苯并咪唑的5位存在亲脂性取代基与细胞毒性增强相关。虽然尚未评估在5位和6位同时有取代基的影响，但先前的研究确实表明，在5,6位存在稠合苯环会导致拓扑异构酶I抑制活性和细胞毒性显著降低。在本研究中，我们研究了各种三苯并咪唑在5位和6位的取代基是否能保留拓扑异构酶I抑制活性。合成了5-溴-和5-苯基三苯并咪唑的6-溴、6-甲氧基或6-苯基衍生物，并评估了它们的拓扑异构酶I抑制活性以及对人淋巴瘤细胞的细胞毒性。数据表明，这些衍生物确实保留了相似的拓扑异构酶I抑制活性，并且具有与5-溴-或5-苯基三苯并咪唑相当的细胞毒性。当2"-位被氯或三氟甲基取代时，观察到5-苯基三苯并咪唑的拓扑异构酶I抑制活性和细胞毒性显著增强。还探讨了这些取代基对5,6-二溴三苯并咪唑（6a）生物活性的影响。就2"-氯-5,6-二溴三苯并咪唑（6b）或2"-三氟甲基-5,6-二溴三苯并咪唑（6c）而言，相对于6a，拓扑异构酶I抑制作用并未增强。虽然对RPMI 8402的细胞毒性也没有受到显著影响，但针对几种人类实体瘤细胞系进行的比较研究确实表明，与6a相比，6c的细胞毒性显著增加。
