Stereocontrolled synthesis and evaluation of functionalized lactams as potential anti-triple-negative breast cancer agents

Triple-negative breast cancer (TNBC) is an aggressive subtype compromising ~ 10-15% of cases and defined by loss of ER, PR, and HER2, leading to limited therapies. Chemoresistance and tumor heterogeneity underscore the need for new small-molecule agents. Medicinal chemists note that stereocenters enhance drug potential; thus, chiral N-based cyclic compounds like lactams are valued. Here, we report the synthesis and anticancer evaluation of functionalized lactams bearing four contiguous stereocenters against TNBC models.A diversity-oriented synthesis strategy generated 40 structurally varied lactams. Compounds were screened for cytotoxicity against three TNBC (MDA-MB-231, BT-549, and 4T1) and one normal breast epithelial (MCF10A) cell lines using MTT assay. Clonogenic, wound-closure, ROS and Boyden chamber assays assessed growth and migration. Compounds with strong cancer-cell cytotoxicity and low MCF10A toxicity were selected for further analysis. Mechanistic data were obtained via immunoblotting and immunofluorescence for apoptosis markers. SwissADME was used for pharmacokinetic and drug-like predictions.Multiple lactams showed potent antiproliferative activity with sub-micromolar IC₅₀ values, identifying W11, W12, and W23 as the most active, with IC₅₀ values of (28.8, 40.8, and 28.4) μM in 4T1; (40.7, 38.7, and 21.6) μM in MDA-MB-231; and (22.2, 28.7, and 28.6) μM in BT-549. Lead compounds W11, W12, and W23 with cisplatin as control, significantly and dose-dependently reduced ROS, clonogenicity and migration, indicating anti-metastatic potential. W11 had the lowest EC₅₀ (~23 µM), while W12, W23, and cisplatin showed EC₅₀ values around 30-34 µM. These results indicate that the lead compounds reduce viability and impair TNBC cell motility. Mechanistic studies revealed robust activation of apoptosis pathways. SwissADME predicted high GI absorption, optimal lipophilicity (LogP<5), Lipinski compliance, and favorable biodegradability.This study identifies lactams W011, W012, and W023 as promising small-molecule candidates for TNBC. Their modulation of apoptotic and other pathways such as ROS-induction, along with favorable predicted pharmacokinetics, supports further preclinical optimization and development toward targeted TNBC therapy.