2,3-Dimethoxybenzo[ i]phenanthridines: topoisomerase I-targeting anticancer agents

Abstract

Appropriately substituted benzo[ i]phenanthridines structurally related to nitidine, a benzo[ c]phenanthridine alkaloid with antitumor activity, are active as topoisomerase I-targeting agents. Studies on benzo[ i]phenanthridines have indicated analogues that possess a 2,3-methylenedioxy moiety and at least one and preferably two methoxyl groups at the 8- and 9-positions, such as 8,9-dimethoxy-2,3-methylenedioxybenzo[ i]phenanthridine, 2, are active as topoisomerase I-targeting agents. Tetramethoxylated benzo[ i]phenanthridines, wherein the 2,3-methylenedioxy moiety is replaced with methoxyl groups at the 2- and 3-position, are inactive as a topoisomerase I-targeting agent. These results initially suggested that the 2,3-methylenedioxy moiety was critical to the retention of potent activity. Further studies revealed that 2,3-dimethoxy-8,9-methylenedioxybenzo[ i]phenanthridine, 7a, is more potent than 2 as a topoisomerase I-targeting agent. The observation that 2,3-dimethoxylated benzo[ i]phenanthridines can actually exhibit enhanced activity prompted the present study in which several 8-substituted 2,3-dimethoxybenzo[ i]phenanthridines were prepared and their pharmacological activities evaluated. The influence of NH 2, CN, CH 2OH, OBn, OCH 3, OH, and NHCOCH 3 substituents at the 8-position on the relative activity of these 2,3-dimethoxybenzo[ i]phenanthridines was examined. Relative to these derivatives, 7a was the most potent topoisomerase I-targeting agent, possessing similar cytotoxicity to that of nitidine in the human lymphoblast tumor cell line, RPMI8402.