Design, synthesis and biological evaluation of Chidamide derivatives against breast cancer.

In this study, we designed and synthesized a series of compounds derived from the histone deacetylase inhibitor (HDACi) Chidamide and the BET bromodomain inhibitor (+)-JQ-1. All target compounds were structurally characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). Antiproliferative activity was assessed by an MTT assay in MDA-MB-231 (breast cancer), HeLa (cervical cancer), and HCT116 (colon cancer) cells, with chidamide and (+)-JQ-1 as reference compounds; cytotoxicity in 293 T cells was further evaluated to estimate selectivity. Results indicated that most derivatives exhibited superior activity to Chidamide, with compound 6e demonstrating the strongest inhibitory effect against MDA-MB-231 cells. The IC50 values of 6e were 0.10 ± 0.02 μM (MDA-MB-231), 0.90 ± 0.17 μM (HeLa), 19.60 ± 0.90 μM (HCT116), and 70.13 ± 5.19 μM (293 T). Further assays showed that 6e inhibited colony formation, migration, adhesion, and invasion of MDA-MB-231 cells in a concentration-dependent manner. Annexin V-FITC/PI flow cytometry indicated apoptosis induction. In the chicken embryo chorioallantoic membrane (CAM) model, 6e inhibited tumor growth and angiogenesis more effectively than chidamide. In summary, 6e demonstrates promising optimization potential as a lead compound for breast cancer therapy.