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 6a, 6b, 6d, and 6f 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 7a-f 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 6a, 6b, and 6f significantly reduced the clonogenic capacity of TNBC cells and induced reactive oxygen species (ROS). Notably, compounds 6b and 6f 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.