Akademik Veri Yönetim Sistemi
JOURNAL OF MOLECULAR STRUCTURE, cilt.1354, 2026 (SCI-Expanded, Scopus)
Breast cancer remains one of the most prevalent and lethal malignancies among women, highlighting the urgent need for novel therapeutic strategies that can overcome resistance mechanisms. The p38 alpha mitogen-activated protein kinase (MAPK14) plays a key role in inflammation-associated oncogenic signaling, making it an attractive molecular target for drug development. In this study, a novel series of diclofenac-based hydrazone derivatives (4a-4o) were designed, synthesized, and characterized using FT-IR, 1H- and 13C-NMR spectroscopy, thin-layer chromatography, and elemental analysis. Computational target profiling using SwissTargetPrediction identified MAPK14 as the primary predicted target. Molecular docking against the MAPK14 crystal structure (PDB ID: 1WBS) revealed high binding affinities (-11.41 to -8.34 kcal/mol), supported by MM/GBSA free energy calculations and molecular dynamics simulations, which confirmed stable ligand-protein interactions through hydrogen bonding with Asp168 and Glu71. In vitro cytotoxicity assays on MCF-7 (luminal A) and MDA-MB-231 (triple-negative) breast cancer cell lines demonstrated low-micromolar IC50 values, with compounds 4c, 4d, and 4e showing the strongest activity (2.1-4.5 mu M), surpassing the reference drug Tamoxifen. Overall, the results indicate that diclofenac hydrazones represent promising candidates anticancer properties through MAPK14 inhibition, providing a foundation for the development of next-generation therapeutics against breast cancer.