Design, synthesis, biological evaluation, and computational studies of new bis-imine transition metal complexes as anticancer agents
Hatice Gamze Sogukomerogullari, Gulay Dilek, Bulent Dede, Sadeq K. Alhag, Senem Akkoc
article (Uluslararası, Hakemli) | Yazar(lar): Hatice Gamze Sogukomerogullari, Gulay Dilek, Bulent Dede, Sadeq K. Alhag, Senem Akkoc | Yıl: 2027 | Dergi/Kurum: JOURNAL OF MOLECULAR STRUCTURE | İndeks: WOS.SCI | DOI: 10.1016/j.molstruc.2026.147373 | Anahtar Kelimeler: Schiff base, Transition metal complexes, DFT, Cytotox
A bis-imine Schiff base ligand (H2L) and its novel Fe(II), Ni(II), Cu(II), Pd(II), and Pt(II) complexes were synthesized and evaluated for their anticancer potential through combined experimental and computational approaches. Cytotoxic activities were assessed against human cancer cell lines together with normal L929 fibroblasts. Although the Fe(II) and Pt(II) complexes exhibited the strongest antiproliferative activities, the Pt(II) complex demonstrated the highest selectivity toward cancer cells, with selectivity index (SI) values of 5.74 for DLD-1 and 9.66 for A549, markedly exceeding that of cisplatin against A549 cells. To elucidate the structure-activity relationship (SAR) at the molecular level, density functional theory (DFT) calculations were performed at the B3LYP/6-311G(d,p) and B3LYP/LANL2DZ level of theory. The results demonstrated that metal coordination significantly modifies the electronic structure, reduces the HOMO-LUMO energy gap, and enhances electronic delocalization, particularly in the Pd(II) and Pt(II) complexes. Molecular electrostatic potential (MEP), total density of states (TDOS), and thermodynamic analyses further confirmed increased structural rigidity and electronic stabilization upon complex formation. Molecular docking studies targeting the kinase domain of 4UYA revealed favorable binding affinities for all complexes, with the Fe(II) complex displaying the lowest binding energy (-11.2 kcal/mol). Key interactions with residues such as LYS172, THR171, and MET182 were identified as major contributors to binding stabilization. To validate docking predictions, a 100 ns molecular dynamics simulation was performed for the FeL-4UYA complex. The stability of the system was confirmed by consistent RMSD, RMSF, radius of gyration, SASA, and hydrogen-bonding profiles, and by the preservation of secondarystructure elements throughout the trajectory. Overall, the integrated computational and biological findings underscore the significant potential of these metal-coordinated Schiff base frameworks for targeted cancer therapy.