Abstract
Breast cancer continues to pose a major worldwide health concern, characterized by its complexity and the diverse nature of its molecular subtypes. Among these, triple-negative breast cancers (TNBCs) present a formidable obstacle due to their aggressive progression and lack of targeted hormonal therapies. Molecular hybridization is a compelling strategy in drug design and development, combining distinct bioactive components to enhance potency and selectivity. Herein, we present the design and synthesis of a new series of pyrido-indole-one hybrids featuring a β-carboline core, by utilizing the molecular hybridization strategy, integrating indole-2-carboxamides with ynone functionalities to mitigate TNBC progression. A novel synthetic approach has been devised for synthesizing hybrid molecules, employing annulation of indole-2-carboxamides with ynones, facilitated by a Ru-complex catalyst. All the reaction conditions are meticulously optimized to yield the target hybrid molecules. Among the synthesized hybrids, 9c exhibits strong anticancer potency against MCF-7, 4T1 and MDA-MB-231 breast carcinoma cell lines with IC50 values of 4.34 ± 0.31 μM, 3.71 ± 0.39 μM and 0.77 ± 0.03 μM respectively. Moreover, compound 9c exhibits IC50 values of 7.96 ± 0.04 μM and 7.18 ± 0.32 μM in normal HEK-293 kidney cells and BEAS-2B lung cells respectively, indicating ∼10-fold preference for highly aggressive MDA-MB-231 breast cancer cells. Further analyses demonstrated that compound 9c effectively induces cell cycle arrest in MCF-7, 4T1 and MDA-MB-231 breast cancer cells, subsequently leading to a dose-dependent increase in apoptotic cell death. In addition, compound 9c also attenuated the formation of three-dimensional multicellular tumor spheroids (MCTSs), indicating its potential to hinder spheroid development. The molecular docking analysis further elucidates the binding affinity of 9c toward epidermal growth factor receptor (EGFR). As a result, the active hybrid 9c demonstrates strong potential in engaging key cancer-related pathways, further emphasizing its significance in the advancement of next-generation anticancer therapeutics.