Design, synthesis, and biological evaluation of imidazophenanthrolines as human topoisomerase I inhibitors

Cancer remains one of the major health challenges worldwide, highlighting the need for new and more effective therapeutic strategies. Among the molecular targets identified for cancer therapy, human topoisomerase I (TOP1) is a clinically validated target. The camptothecin (CPT) derivatives irinotecan and topotecan exert their antitumoral activity by targeting TOP1. However, despite their clinical efficacy, these drugs present important limitations, including severe side effects, the development of resistance, and the instability of the pharmacologically active lactone ring under physiological conditions. Therefore, the development of novel, structurally CPT-unrelated TOP1 inhibitors represents a promising strategy for anticancer drug discovery.

CPT derivatives and several other reported TOP1 inhibitors share a common structural feature consisting of a planar polycyclic core with an extended π-conjugated system. Based on these characteristics, we designed a series of imidazophenanthrolines and evaluated their potential as TOP1 inhibitors.

Herein, we report the synthesis and characterization of these compounds together with their biological evaluation. DNA relaxation assays revealed an irreversible TOP1 inhibition profile, in contrast to the reversible mode of action displayed by CPT. Moreover, the compounds showed promising antiproliferative activity against A549 lung carcinoma cells, with IC₅₀ values ranging from the low micromolar to the nanomolar range. Evaluation of selective toxicity towards lung carcinoma cells further identified several compounds displaying greater selectivity than the reference compound CPT.

Overall, these results support imidazophenanthrolines as promising scaffolds for the development of novel CPT-unrelated TOP1-targeting anticancer agents.