Design, synthesis of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivatives as potential anticancer agents.

The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overcome these limitations, we designed a series of novel THβC derivatives via molecular hybridization at the N-2 site using natural unsaturated carboxylic acids, aiming to improve solubility and biological activity. Among the synthesized compounds, derivative 9 exhibited potent and selective anti-proliferative activity against MCF-7 breast cancer cells. Based on this promising activity, we first investigated its effect on key oncogenic pathways. Western blot analysis revealed that compound 9 significantly downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) without affecting the NF-κB p65 subunit, suggesting a selective mechanism of action. Subsequent molecular docking studies provided a structural rationale for this selectivity, showing favorable binding modes of 9 within the ERK1/2 kinase domains. Collectively, this work establishes N-2 functionalization as a viable strategy for developing THβC-based anticancer agents with optimized pharmacological profiles.