Synthesis and Evaluation of Novel Fluorinated Quinoline Derivatives in 2D and 3D Models of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer that is more likely to metastasize and become resistant with a worse prognosis. Herein, we have synthesized novel fluorinated quinoline analogues and investigated their anticancer properties against breast cancer cell lines and cancer cell spheroids. Compounds <b>6a</b>, <b>6b</b>, <b>6d</b>, and <b>6f</b> demonstrated potent anticancer activity with IC₅₀ values of 2.5-5 μM against TNBC cells (MDA-MB-468), while remaining nontoxic to nontumorigenic breast cells (MCF-10A). The hydrolyzed analogues <b>7a-f</b> were not active against TNBC cells, implying that the ester group together with fluorine substitution on the quinoline ring is critical for their anticancer activity. Compounds <b>6a</b>, <b>6b</b>, and <b>6f</b> significantly reduced the clonogenic capacity of TNBC cells and induced reactive oxygen species (ROS). Notably, compounds <b>6b</b> and <b>6f</b> considerably decreased TNBC cells (MDA-MB-468 and 4T1) 3D spheroids volume. The present research opens new avenues for developing novel therapeutics for breast cancers.