Synthesis and evaluation of 8-(benzyloxy)-5,7-dibromo-2-methylquinoline derivatives as inducers of apoptosis in triple-negative breast cancer MDA-MB-468 cells via MKK7-JNK pathway activation

To discover novel anti-cancer agents, a total of twenty derivatives of 8-hydroxyquinoline were synthesized by alkylation and benzylation of 8-hydroxyl-5,7-dibromo-2-methylquinoline. The anti-cancer activity of these compounds against triple-negative breast Cancer (TNBC) cells MDA-MB-468, lung Cancer cells A549, and liver Cancer cells HepG2 were evaluated using MTT assay. Among them, compounds 10k and 10l exhibited profound effects against MDA-MB-468 cells with IC₅₀ values less than 1 μM. The most potent one, compound 10l, was found to significantly inhibit the proliferation and migration of MDA-MB-468 cells. It also induced Apoptosis in MDA-MB-468 cells, as evidenced by Hoechst staining, flow cytometry, and Western blot analysis. Treatment with 10l significantly increased phospho-JNK (p-JNK) levels, and blockage of JNK signaling by either pharmacological inhibitor SP600125 or JNK siRNA abolished its pro-apoptotic effect, demonstrating that JNK activation was critical for 10l-induced cell death. Notably, the major kinase upstream of JNK MKK7 was activated under 10l treatment. All these data suggested that compound 10l was capable of inducing Apoptosis via activating MKK7-JNK pathway, supporting its potential as a therapeutic candidate for TNBC treatment.

8-Hydroxyquinoline; Apoptosis; Broquinaldol; JNK pathway; Triple negative breast Cancer.