Synthesis and exploration of breast cancer agent from curcumin analogs based on 3-benzyloxybenzaldehyde

This study aims to explore potential anticancer drug candidates by conducting synthesis, cytotoxic activity, and immunocytochemistry against T47D, HER2, MCF-7, and 4T1 breast cancer cell lines, along with bioinformatics analysis, molecular docking, and ADMET (absorption, distribution, metabolism, excretion, toxicity) studies. Synthesis of curcumin analogs was carried out by reacting 3-benzyloxybenzaldehyde and piperidone derivatives through aldol condensation, while structure elucidation was analyzed with Fourier transform infrared (FTIR) and nuclear magnetic resonance ( 1 H-NMR and 13 C-NMR) instruments. In vitro analysis revealed that curcumin analogs C1 and C2 had cytotoxic activity (IC 50 ), of which C1 was the highest at 5.45 μg/mL against 4T1 and C2 at 1.75 μg/mL against HER2. The selectivity index indicates that C1 reveals high selectivity on 4T1 cell lines, while C2 is not selective against all breast cancer cell lines. A critical step in tumor initiation and progression is the evasion of apoptosis, a process tightly regulated by proteins such as p53 and BCL-2, which play pivotal roles in controlling cellular survival and programmed cell death. Immunocytochemistry shows the expression of p53 and BCL-2 proteins from C1. Treatment with C1 at 2.725 μg/mL increased p53 protein expression by 86.36% in the 4T1 cell line. In T47D cells, BCL-2 expression decreased slightly at C1 concentrations of 28.34 and 14.17 μg/mL. The pharmacokinetic profile showed increased absorption, tissue distribution, and lower toxicity than curcumin. The main target protein signaling pathways in breast cancer for compounds C1 and C2 can be identified by integrating biological networks, pharmacological data, and molecular interactions, providing insights into potential therapeutic strategies. The outcomes of this study identified that AKT1 is the primary target protein for the curcumin analog compounds C1 and C2. Inhibition of AKT1 activation by compounds C1 and C2 may represent a promising therapeutic strategy for the treatment of breast cancer. However, due to its lack of selectivity, C2 is best considered a lead compound for optimization, whereas C1 demonstrates both cytotoxicity and selectivity, making it the stronger therapeutic candidate. For further development, it is recommended to conduct direct experimental studies in the laboratory to confirm the role of AKT1 as the main molecular target.