Graphical abstract Biological evaluation of N5-substituted benzo[c]phenanthrolines and C6-substituted benzo[c]phenanthrolinones shows interessant cytotoxicity associated with some DNA interactions. However, the low topoisomerase 1 affinity suggests that other cellular targets are involved. Highlights ► Pharmacomodulation of natural alkaloids to improve their profiles as anticancer agents. ► New generation of aza-analogues: benzo[c]phenanthrolines and benzo[c]phenanthrolinones. ► Introduction of dialkylaminoalkyl chains. ► Replacement of a benzene by a pyridine. ► Increased cytotoxicity and DNA affinity.