Design, synthesis, and in vitro antiproliferative activity of novel 4-amino-6-phenoxyquinoline and 4,6-diphenoxyquinoline

Abstract

This study aimed to synthesize and biologically evaluate novel 4-amino-6-phenoxyquinoline and 4,6-diphenoxyquinoline derivatives with potential anticancer activity. The newly synthesized compounds were screened for cytotoxicity against a panel of seven human cancer and normal cell lines using the MTT assay to determine IC₅₀ values, with sorafenib included as a reference drug. Among the tested molecules, compounds 7a and 7b demonstrated the most potent and selective reduction in cell viability, particularly in A549 lung carcinoma, PANC-1 pancreatic cancer, and MCF-7 breast cancer cells, and were therefore selected for further mechanistic investigations. Flow cytometry-based Annexin V/PI analysis revealed significant induction of apoptosis and necrosis following treatment, with pronounced effects observed in A549 and PANC-1 cells exposed to compound 7a and sorafenib. Acridine orange staining further confirmed a marked increase in autophagic activity across all examined cancer cell lines, indicating the activation of additional cell death pathways. Cell cycle analysis demonstrated compound- and cell-type-dependent effects, including S-phase arrest in A549 and PANC-1 cells and G1-phase arrest in MCF-7 cells. Collectively, these findings indicate that 4-amino-6-phenoxyquinoline derivatives exert anticancer effects through coordinated induction of apoptosis, autophagy, and cell cycle arrest, supporting their potential as promising candidates for further anticancer drug development.