Design, synthesis, and biological evaluation of novel trifluoromethyl-substituted quinolinone derivatives targeting triple-negative breast cancer.

To develop more effective chemotherapeutic agents capable of simultaneously suppressing the growth and metastasis of triple-negative breast cancer (TNBC), a series of novel trifluoromethyl-substituted quinolinone derivatives were synthesized via a visible-light-promoted coupling reaction between coumarin/quinolinone precursors and α-trifluoromethylalkyl bromides. All newly synthesized compounds were fully characterized by 1H NMR, 13C NMR, 19F NMR and high-resolution mass spectrometry. The lead candidate (3a) was obtained, which exhibited potent cytotoxicity to TNBC cell line MDA-MB-231. Furthermore, 3a potently suppressed colony formation and three-dimensional spheroid growth, while markedly inhibited MDA-MB-231 migratory and invasive capacities. Notably, 3a exhibited superior antitumor and anti-metastatic activity in vivo than Paclitaxel. Mechanistic studies revealed that 3a induced apoptosis by regulating the BCL-2/Caspase-3 pathway and suppressed metastasis through downregulating the expression of VEGFR-2, MMP-2, and MMP-9.