Abstract 1000: Stereocontrolled synthesis and evaluation of functionalized lactams as potential anti-triple-negative breast cancer agents

Abstract 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 (LogP5), 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. Citation Format: Leila Rahimian, Tolulope Omolekan, Ojasvi Dutta, Konstantin G. Kousoulas, Timothy K. Beng, Jean C. Chamcheu. Stereocontrolled synthesis and evaluation of functionalized lactams as potential anti-triple-negative breast cancer agents abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1000.