Illuminating anticancer pathways with pyrene Schiff bases: bridging simulations and experiments

Abstract

Cytochrome P450 1A1 (CYP1A1) plays a key role in the metabolic activation of carcinogens, making its inhibition a promising chemopreventive strategy. In this study, three pyrene-1-carboxaldehyde-derived Schiff bases, PEBD, APSB, and PyAP were investigated as potential CYP1A1 inhibitors using an integrated computational and experimental approach. Density functional theory (DFT) calculations, molecular docking, molecular dynamics (MD) simulations, and ADME analyses were performed to elucidate their structural features, binding interactions, and drug-likeness. The compounds exhibited strong binding affinities toward CYP1A1, with PEBD showing the highest docking score (–13.89 kcal/mol) and MD binding energy (–41.13 ± 4.07 kcal/mol). Ethidium bromide displacement assays confirmed efficient intercalation into CT-DNA (Kb = 1.54 × 10⁴ M⁻¹ for PEBD). MTT assays revealed that PEBD exerted the strongest cytotoxicity toward breast cancer cell lines MCF-7 (IC₅₀ = 23.9 μM) and MDA-MB-231 (IC₅₀ = 36.7 μM), while remaining non-toxic to normal MCF-10A cells. Overall, these findings highlight PEBD as a promising polycyclic aromatic Schiff base scaffold for the development of CYP1A1-targeted chemopreventive agents against breast cancer.