A systematic study of nitrated indenoisoquinolines reveals a potent topoisomerase I inhibitor

The biological activity of indenoisoquinoline topoisomerase I inhibitors is significantly enhanced by nitration of the isoquinoline ring. In the present study, nitrated analogues were synthesized with the indenone ring substituted with methoxy groups to further explore a previously identified structure-activity relationship between the nitrated isoquinoline ring and a methylenedioxy-substituted indenone ring. The results indicate that a single methoxy group at the 9-position of an indenoisoquinoline affords superior biological activity. Hypothetical binding models have been developed to rationalize these results, and they indicate that pi-stacking between the indenoisoquinolines and the DNA base pairs, as visualized by electrostatic complementarity, is important for the intercalation and biological activity of the indenoisoquinoline analogues. Collectively, the analysis of methoxy groups on the indenone ring also illustrates a strict steric requirement for substituents extending toward the nonscissile DNA backbone and emphasizes a need for planarity to afford potent biological activity.