Structure-activity modulation of nitro-substituted bis(acylhydrazone) ligands by O-alkylation in breast cancer models
Journal of Molecular Structure, vol.1375, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 1375
- Publication Date: 2026
- Doi Number: 10.1016/j.molstruc.2026.146934
- Journal Name: Journal of Molecular Structure
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Keywords: Apoptosis, Bis(acylhydrazone) ligands, Breast cancer, Molecular docking, O-alkylation, Structure-activity relationship
- Hacettepe University Affiliated: Yes
Abstract
A minimal and controlled chemical modification strategy was employed to elucidate the structure-activity relationship of nitro-substituted bis(acylhydrazone) ligands in breast cancer models. A parent ligand (HL1) and its O-alkylated derivatives (HL2 and HL3) were synthesized and characterized by spectroscopic methods, elemental analysis and single-crystal X-ray diffraction (HL1 and HL2) supported by Hirshfeld surface analysis. Notably, a single and well-defined O-alkylation step, without altering the hydrazone core, resulted in a pronounced and systematic enhancement of biological activity. While the non-alkylated ligand HL1 was inactive (IC50>200 µM), HL2 and HL3 exhibited low micromolar antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cells (IC50 = 4.3–9.6 µM) with moderate selectivity over non-cancerous HEK293 cells. Clonogenic and flow cytometric analyses indicated that the observed effects were primarily associated with induction of cell death. Gene expression profiling revealed modulation of key apoptotic regulators, including downregulation of AKT, BCL2 and BIRC5 and upregulation of BAX, CDKN1A and TP53. Complementary in silico target prediction and molecular docking analyses suggest the involvement of kinase-associated survival pathways, including GSK3β-related signaling. Overall, these findings demonstrate that minimal and precisely controlled O-alkylation is sufficient to induce a distinct shift in biological activity, establishing a direct and chemically driven structure-activity relationship in nitro-functionalized bis(acylhydrazone) systems.