Discovery of α-carboline fused benzofuran-containing anticancer agents as rapid apoptosis inducers through intrinsic pathway

Apoptosis, a programmed form of cell death, typically requires several hours to initiate cytochrome c release following stimuli. Facilitating Apoptosis plays a decisive role in eliminating detrimental cells as well as in Cancer treatment. In this study, diverse novel α-carboline-fused benzofuran collections were efficiently achieved via C-H activation/Lossen rearrangement/[4 + 2] cyclization cascades. Among them, compound 10 was found to rapidly induce Apoptosis through the intrinsic pathway by releasing cytochrome c within 10 min, followed by cleavage and activation of caspase-9, Caspase-3, and PARP1. Mechanistically, compound 10 was found to potently inhibit several signaling cascades that are important for cell proliferation and survival, including Akt, ERK1/2, STAT1, STAT3, and S6K, suggesting its role as a multi-kinase inhibitor in inducing rapid Apoptosis. Furthermore, compound 10 significantly inhibited tumor growth in a mouse xenograft model. Overall, this novel inducer of rapid Apoptosis may serve as a powerful tool for further elucidation of apoptotic mechanisms and holds promising therapeutic potential in clinical Cancer treatment.