Abstract / Summary
Background/Objectives: Ovarian cancer remains one of the deadliest gynecological malignancies due to late diagnosis, frequent recurrence, and the development of resistance to platinum-based chemotherapy. Naphthyridines constitute a diverse class of heterocyclic compounds with promising anticancer properties. The aim of this study was to evaluate the anticancer activity of three structurally related 2,7-naphthyridine derivatives (Naph-1, Naph-2, and Naph-3), identify the most active compound, and investigate its mechanism of action in ovarian cancer models. Methods: Cytotoxic activity was evaluated using the PrestoBlue assay in human cancer cell lines IGROV-1, MDAH-2774, SKOV-3, K562, MCF-7, and A549 and a non-cancerous CHO-K1 cell line. The most active derivative, Naph-3, was subsequently characterized in the two most sensitive ovarian cancer models (IGROV-1 and MDAH-2774) by evaluating its effects on 3D spheroid viability, cell proliferation, migration, apoptosis, and cell cycle progression. Electrochemical impedance spectroscopy was used as a label-free method for real-time monitoring of treatment-induced cellular responses. Cisplatin served as the reference compound. Results: Among the tested derivatives, Naph-3 demonstrated the strongest anticancer activity, with the highest sensitivity observed in ovarian cancer cell lines IGROV-1 (IC50 30.31 µM) and MDAH-2774 (IC50 53.68 µM). Naph-3 inhibited cell proliferation and migration, induced G1-phase cell cycle arrest, and promoted apoptotic cell death in both IGROV-1 and MDAH-2774 cells. In 3D spheroid models, Naph-3 retained significant activity in IGROV-1 spheroids, whereas MDAH-2774 spheroids displayed pronounced resistance to treatment. Although Naph-3 was less potent than cisplatin, it exhibited greater selectivity toward cancer cells, with lower toxicity against non-cancerous CHO-K1 cells. Impedance spectroscopy in a wide frequency range provided complementary kinetic information, supporting the interpretation that Naph-3 exerts a predominantly cytostatic effect, whereas cisplatin induces a more pronounced cytotoxic response. Conclusions: Naph-3 emerged as the most promising derivative among the tested compounds and exhibited multifaceted anticancer activity in IGROV-1 and MDAH-2774 ovarian cancer models. Its favorable selectivity profile, combined with antiproliferative, pro-apoptotic, and anti-migratory properties, highlights its potential as a promising compound for the development of novel therapeutic strategies against ovarian cancer.