Abstract
This study reports the synthesis, cytotoxic evaluation, and mechanistic insights of an amphiphilic triamino glycosylated antitumor ether lipid (GAEL). A series of aryl-substituted tricationic d-galacto-GAELs were synthesized to mimic cationic amphiphilic drug (CAD)-like structural characteristics. Among the series, the quinoline-bearing triamino GAEL (compound 17) exhibited the highest cytotoxicity in 2D cultures against drug-sensitive and drug-resistant ovarian, breast, pancreatic, liver, prostate, and brain cancer cells, completely eliminating all cells, whereas cisplatin and doxorubicin were less effective. GAEL 17 also demonstrated superior efficacy in an SK-OV-3 3D tumor spheroid model, fully disintegrating spheroids and inducing cell death at concentrations ≥25 μM. In contrast, doxorubicin reduced viability but did not eradicate spheroids at 50 μM, likely due to slower drug action or limited penetration over 48 h exposure. GAEL 17 retained caspase-independent, non-apoptotic cell death. LysoTracker assay indicated lysosomal disruption, while LipidTOX staining showed dose-dependent fluorescence, consistent with CAD-like lipid accumulation.